Existing and investigational therapies for the treatment of Clostridium difficile infection: A focus on narrow spectrum, microbiota-sparing agents

Existing and investigational therapies for the treatment of Clostridium difficile infection: A focus on narrow spectrum, microbiota-sparing agents

Disponible en ligne sur ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 48 (2018) 1–9 General review Existing and investigati...

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ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 48 (2018) 1–9

General review

Existing and investigational therapies for the treatment of Clostridium difficile infection: A focus on narrow spectrum, microbiota-sparing agents Traitements actuels et expérimentaux dans la prise en charge des infections à Clostridium difficile : agents à spectre étroit épargnant le microbiome H.G. Maxwell-Scott , S.D. Goldenberg ∗ London and Guy’s and St Thomas’ NHS Foundation Trust, Centre for Clinical Infection and Diagnostics Research, King’s College, London, United Kingdom Received 14 September 2017; accepted 23 October 2017 Available online 21 November 2017

Abstract Despite intense international attention and efforts to reduce its incidence, Clostridium difficile infection (CDI) remains a significant concern for patients, clinicians, and healthcare organizations. It is costly for payers and disabling for patients. Furthermore, recurrent CDI is particularly difficult to manage, resulting in excess mortality, hospital length of stay, and other healthcare resource use. A greater understanding of the role of the gut microbiome has emphasized the importance of this diverse community in providing colonization resistance against CDI. The introduction of fidaxomicin, which has limited effect on the microflora has improved clinical outcomes in relation to disease recurrence. There are a number of other new agents in development, which appear to have a narrow spectrum of activity whilst exerting minimal effect on the microflora. Whilst the role of these emerging agents in the treatment of CDI is presently unclear, they appear to be promising candidates. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Clostridium difficile; Metronidazole; Vancomycin; Fidaxomicin; Cadazolid; Ridinilazole; CRS3123; LFF517

Résumé Malgré l’attention internationale et les efforts entrepris pour réduire leur incidence, les infections à Clostridium difficile (ICD) restent une préoccupation majeure pour les patients, les médecins et les organismes de santé. Les ICD coûtent cher et sont invalidantes pour les patients. De plus, les ICD récurrentes sont particulièrement difficiles à traiter, entraînant une augmentation de la mortalité, de la durée du séjour hospitalier et du recours à d’autres ressources de soin. Une meilleure compréhension du rôle du microbiome intestinal a mis en évidence l’importance de cette communauté variée dans le développement d’une résistance à la colonisation contre les ICD. La mise sur le marché de la fidaxomicine, dont les effets sur la microflore sont limités, a permis d’améliorer les résultats cliniques relatifs à la récidive de l’infection. De nombreux autres agents sont actuellement en développement ; ces derniers semblent avoir un spectre étroit et leurs effets sur la microflore semblent être très limités. Bien que le rôle de ces nouveaux agents dans le traitement des ICD reste incertain, ils semblent tout de même prometteurs. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Clostridium difficile ; Métronidazole ; Vancomycine ; Fidaxomicine ; Cadazolide ; Ridinilazole ; CRS3123 ; LFF517



Corresponding author. E-mail address: [email protected] (S.D. Goldenberg).

https://doi.org/10.1016/j.medmal.2017.10.008 0399-077X/© 2017 Elsevier Masson SAS. All rights reserved.

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1. Introduction The incidence of Clostridium difficile infection (CDI) has risen significantly during the last 15 years, resulting in substantial morbidity, mortality, and economic burden. Recurrent CDI (rCDI) is especially challenging to prevent and manage, often requiring repeated and prolonged courses of treatment. Uniform consensus on how to effectively manage these patients is lacking. Novel therapeutic strategies are urgently needed to treat patients presenting with or at risk of rCDI. ”Dysbiosis” of the gut microflora and a failure for it to be reconstituted (usually caused by administration of antibiotics) is a significant risk factor for initial CDI and rCDI. Improved antimicrobial stewardship strategies may help to address this problem as well as use of anti-CDI agents that have minimal effect on the microflora, allowing it to recover rapidly. Fecal microbiota transplantation is increasingly being used to prevent further recurrence in patients who have had three or more episodes of infection. Although this approach is efficacious, long-term safety data is lacking and there is little consensus about optimal methods and procedures [1]. In this review current management strategies for CDI are explored together with novel and emerging therapies with a focus on narrow spectrum, microbiota-sparing antibiotics. Other treatment and prevention modalities including fecal microbiota transplantation and augmentation, non-toxigenic C. difficile, antitoxin antibodies (bezlotoxumab), beta-lactamase enzymes (ribaxamase) and toxin-binding agents are beyond the scope of this review. 2. Recurrent Clostridium difficile infection The major underlying risk factor for CDI is an alteration in intestinal microbiota, mainly caused by the administration of antimicrobials. Virtually all classes of antimicrobials have been implicated in precipitating CDI. Persistence of spores that are able to germinate after completion of anti-CDI therapy, continuing suppression of protective intestinal bacteria, and failure to establish an adequate host immune response create the conditions that lead to rCDI. Up to 25 % of patients treated with metronidazole or vancomycin will present with a recurrent episode within 30 days [2–4], and approximately 45–65 % of these will have a further recurrence [5–7]. Rates of recurrence appear to have increased over the past decades, potentially related to the spread of the epidemic BI/NAP1 027 strain. With each recurrent episode comes an increased risk of serious complications including death. In one study rCDI was associated with a six-month mortality rate of 36 %, compared with 26 % in patients without recurrence [8]. A number of risk factors have been identified in patients at increased risk of rCDI: those aged 65 years and older [6,9], those taking proton pump inhibitors (PPIs) and other gastric acid suppressing agents [6], those taking concomitant antimicrobials [6,9], those with renal impairment [6], and those with inflammatory bowel disease [10].

3. Currently available agents to treat Clostridium difficile infection In addition to general supportive measures including discontinuing the inciting antimicrobial(s) and fluid and electrolyte replacement, there are a limited number of anti-CDI agents currently available, each of which will be discussed. An ideal drug for the treatment of CDI should have low systemic absorption, achieve high intraluminal concentrations, preserve the normal microflora, result in high clinical cure rate with low recurrence rate, have low risk for developing resistance, be well tolerated, and be low cost. Currently available agents are assessed against these ideal attributes in Table 1. 4. Metronidazole Metronidazole is a nitroimidazole compound with broadspectrum activity against anaerobic bacteria including C. difficile. However, due to the relatively poor pharmacokinetic properties of oral metronidazole, only low drug levels can be realistically achieved in the lumen of the colon [11]. Additionally, there are concerns over the emergence of reduced susceptibility [12] and at least one documented case of resistance to metronidazole [13]. As it is systemically absorbed and has a number of adverse effects such as nausea and vomiting, taste disturbance, peripheral neuropathy, and a disulfiram-like reaction with alcohol, its use is limited. Several authors have reported relatively poor outcomes and treatment failures with metronidazole [14–16]. The concerns and disadvantages of this agent mean that metronidazole is usually used only for mild, uncomplicated CDI [17–20]. 5. Vancomycin Vancomycin is a glycopeptide, which exerts its effect by inhibition of bacterial cell wall synthesis. When administered orally it is not systemically absorbed. In a study stratifying patients into mild or severe infection and randomizing to receive either metronidazole or vancomycin for 10 days, there was no difference in cure rates between the two drugs (90 % for metronidazole vs. 98 % for vancomycin) in the non-severe cohort. However, in the severe infection group the cure rates were 76 % for metronidazole and 97 % for vancomycin (P = 0.02) [2]. This finding has led to the recommendation to use vancomycin in patients presenting with severe infection in a number of international guidelines [17–20]. However, there is additional (and often overlooked) evidence from a large phase III multicenter randomized controlled trial of tolevamer, a toxin-binding agent, metronidazole and vancomycin, which showed vancomycin to be superior to metronidazole for clinical success (defined as resolution of diarrhea and absence of severe abdominal discomfort due to CDI for more than two consecutive days including Day 10) [21,22].

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Table 1 Relative characteristics of currently available drugs used to treat Clostridium difficile infection. Caractéristiques des traitements actuellement disponibles dans la prise en charge des infections à Clostridium difficile.

Ideal drug Metronidazole Vancomycin Fidaxomicin a

Systemic absorption

Achievable intraluminal concentrations

Ability to preserve normal microflora

Efficacy Efficacy (clinical cure) (prevention of recurrence)

Potential for development of mutational resistance

Tolerability and safety

Cost

Low High Low Low

High Low High High

High Medium Medium High

High Medium High High

Low Mediuma Low Low

High Medium/high High High

Low Low Medium High

High Medium/low Medium High

Reports of increasing minimum inhibitory concentrations.

This study included patients presenting with non-severe CDI and reported rates of clinical success of 72.7 % and 81.1 % for metronidazole and vancomycin respectively (P = 0.02) [21,22]. Additional advantages of vancomycin compared with metronidazole include the ability to achieve high intraluminal concentrations with low levels of systemic absorption (and systemic adverse effects) following oral administration. However, in addition to the high rates of treatment failure, there are concerns over colonization and overgrowth of vancomycin-resistant enterococci in patients treated with this drug [23], as well as concerns about enduring and deleterious effects on the intestinal microbiota. It is thought that extended administration of vancomycin either as a tapering course (stepwise decrease in dose and/or frequency of administration over time) or as pulsed/intermittent dosing, allows reconstitution of normal microflora whilst inhibiting any residual C. difficile spores. There is some evidence that these regimens result in higher cure rates and fewer recurrences compared with standard 10-14-day regimens [5,24].

6. Fidaxomicin Fidaxomicin is an 18-membered first-in-class macrocyclic, derived from the fermentation of a strain of the bacterium Dactylosporangium aurantiacum. Its mode of action is by inhibition of bacterial protein synthesis by blocking RNA polymerase. Fidaxomicin is inactive against Gram-negative bacteria including Bacteroides and Enterobacteriaceae [25]. Due to this narrow spectrum of activity and sparing of many of the predominant bacteria comprising the normal fecal microflora, it appears to limit intestinal dysbiosis when compared with vancomycin [26–28]. Fidaxomicin exerts bactericidal activity against C. difficile and has a prolonged post antibiotic effect after removal of the drug, compared with vancomycin [29,30]. It inhibits spore production [31,32] and toxin production both in vitro [33] and in vivo [34]. Like vancomycin it is very poorly absorbed from the gastrointestinal tract, with negligible detectable plasma levels (less than the lowest limit of detection of 5 ng/mL), and is almost entirely excreted in feces [35]. Intracolonic levels reach approximately 5000 times above the MIC90 [25].

7. Safety and tolerability As fidaxomicin is minimally absorbed from the intestinal tract there is generally limited opportunity for adverse effects in humans. This agent usually appears to be well tolerated. The overall incidence and type of treatment-related adverse effects reported are similar to those seen with oral vancomycin [3,4]. Rarely, hypersensitivity reactions have been reported in the literature with facial, tongue, or throat swelling as the most commonly reported symptoms, which resolved after discontinuation [36]. 8. Clinical efficacy Two identical phase III multicenter randomized controlled clinical trials of fidaxomicin vs. oral vancomycin were reported in 2011 [3] and 2012 [4]. The first multicenter double-blind trial of a 10-day course of fidaxomicin vs. vancomycin (125 mg four times daily) was conducted in North America, and enrolled a total of 629 adult patients presenting with initial CDI or those with a first recurrence [3]. The modified intention-to-treat (mITT) population comprised 596 patients receiving at least one dose of fidaxomicin. The per protocol (pp) population comprised 548 patients receiving at least 3 days of fidaxomicin, who also complied with treatment and underwent end-of-study evaluation. Clinical cure was assessed at the end of therapy (or time of study withdrawal). The rate of recurrence was also assessed for up to four weeks after the end of therapy (defined by the presence of diarrhea and a stool sample positive by toxin assay). Clinical cure rates were similar (fidaxomicin being noninferior to vancomycin), with rates of approximately 88 % and 86 % for fidaxomicin and vancomycin respectively. There was a non-significant trend towards faster time to resolution of symptoms in patients receiving fidaxomicin. Recurrence rates were significantly reduced in fidaxomicin-treated patients compared with vancomycin-treated patients in both the mITT (15.4 % vs. 25.3 %, P = 0.005) and pp groups (13.3 % vs. 24 %, P = 0.004). The second, almost identical phase III study recruited adult patients from Europe as well as North America comprising a total of 509 patients in the mITT population. This also found fidaxomicin to be non-inferior to vancomycin for clinical cure, but recurrence was significantly reduced in fidaxomicintreated patients compared with vancomycin (12.7 % vs. 26.9 %, P = 0.0002 in the mITT group) [4].

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Whole genome sequencing studies of the isolates obtained from patients entered into these two studies have shown that fidaxomicin protects against CDI recurrence both by reducing relapse of infection by the same strain and reinfection with a different strain [37]. This suggests additional benefits in those patients who might be at increased risk of re-exposure, e.g. in a long-term care facility or other healthcare setting. Several post hoc analyses of subgroups using the combined phase III study data, as well as newly acquired data from separate populations, have been performed. A meta-analysis of combined data for 1164 patients in an intention-to-treat analysis showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40 % (95 %CI [26 %–51 %]; P < 0.0001) during up to 40 days of follow-up [38]. Patients who received concomitant antibiotics (27.5 % of patients enrolled in the two studies) had a lower cure rate (84.4 % vs. 92.6 %; P < 0.001) and an extended time to resolution of diarrhea (97 vs. 54 hours; P < 0.001) than those who did not [39]. Furthermore, amongst patients receiving at least one concomitant antibiotic, the cure rate was 90.0 % for fidaxomicin and 79.4 % for vancomycin (P < 0.04) and the recurrence rate was 16.9 % vs. 29.2 %; P < 0.048 respectively [39]. Treatment of first recurrence with fidaxomicin has also been assessed amongst 128 patients who had an episode of CDI in the preceding three-month period [40]. Patients treated with fidaxomicin were significantly less likely to experience a further recurrence than those treated with vancomycin (19.7 % vs. 35.5 % respectively, P = 0.045) [40]. Analysis of a patient sub-population presenting with cancer demonstrated superior cure rate, sustained response, and a faster time to resolution of diarrhea in patients treated with fidaxomicin compared with those treated with vancomycin [41,42]. A sub-population of patients treated in one of the phase III randomized controlled trials of fidaxomicin was found to have less risk of acquiring vancomycin-resistant enterococci (VRE) than those treated with vancomycin (7 % vs. 31 %, P < 0.001), which may have important infection control implications [23].

9. Alternative dosing schedules A recent multicenter randomized open label study compared vancomycin (125 mg four times daily) with an extended-pulsed regimen of fidaxomicin [43]. This consisted of ‘normal dosing’ of 200 mg twice a day for five days, followed by alternate day dosing on days 7–25. This results in the same cumulative dose of fidaxomicin being administered over an elongated period of time. The study recruited 364 patients, comparing sustained clinical cure at 30 days after the end of therapy, which was found to be 59.2 % for vancomycin and 70.1 % for extended-pulsed fidaxomicin (P = 0.03), demonstrating superiority. Rates of recurrence (measured at days 40, 55, and 90 following the end of therapy) were also lower for this novel dosing regimen (19 % for vancomycin compared with 6.2 % for

extended-pulsed fidaxomicin at 90 days after the end of therapy, P < 0.001) [43]. 10. Real-world data A number of post-marketing observational studies have described the use of fidaxomicin in clinical practice in a variety of settings. Vargo et al. studied 61 patients treated with fidaxomicin in a single center in Ohio with 52.5 % having had a previous episode of CDI [44]. Combination CDI therapy was administered to 52.5 % of patients and 31.1 % had severe CDI (defined by the Hines VA Severity Score Index). A total of 72.1 % of patients achieved clinical cure within a median time of 8 days. Clinical cure was significantly higher for patients receiving fidaxomicin monotherapy compared with fidaxomicin combination therapy (25/29 [86.2 %] patients vs. 19/32 [59.4 %] patients, P = 0.04). Overall, recurrence occurred in 6 (13.6 %) of the 44 patients who achieved clinical cure [44]. Another single center study performed in the United States involved patients who were eligible to receive fidaxomicin if they had a recurrent episode, were aged 65 years or older, required concomitant antibiotics, were immunosuppressed, or had laboratory markers of severity [45]. A total of 49 patients received fidaxomicin compared with 46 patients who received oral vancomycin. Significantly fewer patients were readmitted with CDI within 90 days in those receiving fidaxomicin compared with those receiving vancomycin (10/49 [20.4 %] vs. 19/46 [41.3 %], respectively, P = 0.027). This finding was observed even if those receiving fidaxomicin had more prior CDI episodes and were more likely to have moderate or severe CDI [45]. The largest multicenter real-world data study was conducted in seven NHS hospitals in England [16]. This study assessed outcomes associated with fidaxomicin use in 239 patients. This was a before and after study in which each of the hospitals had different criteria for use of fidaxomicin; two of the centers used it as a first-line agent for all episodes, the other five hospitals placed varying degrees of restriction including it as first-line in recurrent episodes only, and in patients who were deemed to be at increased risk of recurrence, e.g. elderly patients, those with multiple comorbidities, those with underlying immunosuppression, those requiring concomitant antibiotics, etc. Recurrence rates were measured for up to three months following discontinuation of therapy, significantly longer than the follow-up period in the phase II registration studies. Although some reductions in the recurrence rate were noted in some of the hospitals that used fidaxomicin selectively, the greatest benefit was seen in the two hospitals using fidaxomicin first line for all episodes. These two hospitals achieved a reduction in the recurrence rate from 10.6 % to 3.1 % and 16.3 % to 3.1 %, respectively. Significantly, the use of fidaxomicin was also associated with a decrease in the 28-day all-cause mortality rate in these two centers (18.2 % to 3.1 % and 17.3 % to 6.3 %, respectively). This suggests that the greatest benefit from this agent can be achieved by using a less restrictive policy. This is in agreement with the views of other authors who have reported that fidaxomicin is less effective for multiply relapsed patients (presumably those with the

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most severely deranged microflora) and should therefore be used early in the course of CDI, rather than in late recurrent disease [46]. Others have reported positive real-world data from a number of patient sub-populations such as those in the intensive care unit (ICU) [47] and solid organ transplant patients [48].

11. Role in environmental contamination and spread Probably related to its bactericidal and sporicidal properties, an additional benefit to using fidaxomicin appears to be its association with a reduced contamination rate into the healthcare environment [49]. A before and after study in a hospital that introduced fidaxomicin for first-line treatment of all CDIs was conducted to assess rates of environmental contamination with spores of C. difficile. Environmental culture samples from 66 patients treated with metronidazole and/or vancomycin were compared with those from 68 patients treated with fidaxomicin. Patients treated with fidaxomicin were less likely to contaminate their environment (25/68, 36.8 %) than patients treated with metronidazole and/or vancomycin (38/66, 57.6 %) (P = 0.02). Widespread use of fidaxomicin could help to limit both the overall burden of CDI and colonization pressure in the healthcare environment.

12. Role in prophylaxis Neither metronidazole nor vancomycin are recommended as prophylactic agents. A small randomized placebo-controlled trial reported that prophylaxis with metronidazole was not effective, and that in patients who were administered oral vancomycin it resulted in a higher rate of carriage at two months [50]. A more recent retrospective cohort study using vancomycin as a prophylactic agent to prevent recurrent CDI in patients requiring systemic antimicrobials has been reported [51]. Use of oral vancomycin prophylaxis resulted in a recurrence rate of 4.2 % compared with 26.2 % in the control group, who did not receive any prophylaxis (OR 0.12, 95 %CI [0.04–0.4], P < 0.001). A further study of 551 CDI episodes treated with concomitant antibiotics reported a decreased risk of recurrence in patients receiving vancomycin prophylaxis compared with those who did not [52]. The concept of antimicrobial prophylaxis to prevent recurrence or even initial infection in very high-risk patients is an attractive one. However, there is concern that this approach may be detrimental to the indigenous microflora. The narrow spectrum of activity of fidaxomicin has led some to suggest a potential role for this agent in prophylaxis. However, a recent randomized clinical trial comparing fidaxomicin (n = 301) with placebo (n = 299) for prevention of initial CDI in patients undergoing hematopoietic stem cell transplant and who required fluoroquinolone prophylaxis, found no evidence of a protective effect with 28.6 % of patients given fidaxomicin developing CDI vs. 30.8 % of patients given the placebo [53].

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13. Health and pharmacoeconomics The high acquisition cost of fidaxomicin when compared with metronidazole and vancomycin has led to reluctance to prescribe this agent widely, despite the clinical evidence to support its effectiveness. As a result, a number of authors have studied the cost effectiveness of fidaxomicin using decision-analytic simulation Markov modeling and other techniques. The cost effectiveness is primarily driven by reducing costs associated with hospitalization and lower recurrence rates compared with vancomycin.

14. Investigational agents There are a number of other agents in various stages of development that appear to exert a narrow spectrum of activity and are relatively sparing of the indigenous colonic microflora.

15. Ridinilazole (SMT19969) Ridinilazole is a novel agent whose mechanism of action is not fully understood, but is thought to work by impairing cell division [54]. It has in vitro activity against C. difficile with at least 1000-fold selectivity over Gram-positive and Gramnegative anaerobic and facultative species of the indigenous gut flora [55]. Although not sporicidal, ridinilazole has been shown to be bactericidal [56] and to inhibit toxin production [54]. In a phase I randomized controlled trial a total of 56 healthy volunteers received escalating doses of the drug up to 2 g per day. Ridinilazole plasma levels were undetectable, and the drug was well tolerated with minimal changes in indigenous gut microflora except Clostridia [57]. A phase II randomized controlled double-blind noninferiority trial compared ridinilazole at a dose of 200 mg twice daily for 10 days with vancomycin (125 mg four times daily for 10 days), recruiting 50 subjects in each arm [58]. This data demonstrated superiority of ridinilazole over vancomycin for sustained clinical response, defined as clinical response at the end of treatment with absence of recurrent disease for the subsequent 30 days (67 % vs. 42 %, respectively). Similarly, clinical response at the end of therapy with an absence of recurrent disease for the next 30 days (sustained clinical response) was also observed to be superior (66.7 % vs. 42.4 %, respectively). In a pre-defined subgroup analysis ridinilazole was associated with improved clinical cure compared with vancomycin for patients aged 75 years and over (83.3 % vs. 22.2 %), those presenting with severe CDI (80 % vs. 37.5 %), those with 1–3 prior CDI episodes (80 % vs. 50 %), and those requiring concomitant antimicrobials (60 % vs. 42.9 %). Recurrent CDI occurred in 34.8 % of patients receiving vancomycin compared with 14.3 % of those receiving ridinilazole. Ridinilazole appeared to be well tolerated with similar rates of adverse effects reported in both groups (82 % in the ridinilazole group and 80 % in the vancomycin group). No adverse effects led to discontinuation of ridinilazole [58].

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Although only a minority of patients recruited into this study had severe disease and/or had a previous episode of CDI, this data is very encouraging [59]. 16. Cadazolid Cadazolid is a novel hybrid fluoroquinolone-oxazolidinone antibiotic which shares structural similarity to linezolid. It works by inhibiting protein synthesis [60] and is bactericidal [61]. It also inhibits sporulation and toxin production [61]. Its spectrum of activity is directed against Gram-positive bacteria with limited impact on the gut flora other than bifidobacteria [62]. There is a very low propensity for development of resistance to cadazolid, and mechanisms of resistance appear to be different from that of linezolid [63]. Similar to fidaxomicin and vancomycin, cadazolid is minimally absorbed and appears to be well tolerated, with low plasma concentrations [64]. In a phase II randomized double-bind trial a total of 84 patients presenting with a first episode or first recurrence were randomized to receive oral vancomycin (125 mg four times daily) or one of three dosing regimens of cadazolid (250, 500, or 1000 mg twice daily) for 10 days [65]. All three dosing regimens resulted in lower recurrence rates than vancomycin (18.2 %, 25 %, 22.2 %, and 50 %, respectively). However, there was no evidence of a cadazolid dosage-dependent response. Two identical phase III international multicenter randomized double-blind studies have completed recruitment in early 2017 and results are expected to be formally reported in 2017 [66,67]. These studies recruited a total of 1263 patients with a primary endpoint of clinical cure rate (resolution of diarrhea [less than or equal to three unformed bowel movements per day for at least two consecutive days with no further need for CDI therapy] at the end of treatment). It has been reported that although the first study met this primary endpoint, the second study (conducted in other countries to the first one) did not [68]. 17. Surotomycin Surotomycin is an oral cyclic lipopeptide acting on the cell membrane and has structural similarity to daptomycin [69]. A phase II non-inferiority study including 209 patients demonstrated lower 28-day recurrence rates when compared with vancomycin (28 % and 17 % for surotomycin 125 mg twice daily and 250 mg twice daily, respectively, compared with 36 % for vancomycin 125 mg four times daily) [70]. However, later efficacy data from a randomized double-blind active-controlled study was unfavorable and further development has been discontinued [71]. 18. LFF571 LFF571 is a semi-synthetic cyclic lipopeptide that interferes with protein synthesis by inhibition of elongation factor Tu (EFTu) [72]. It has potent in vitro activity against C. difficile and most other Gram-positive anaerobes except bifidobacteria and

lactobacilli [73] and has been shown to be more effective than vancomycin in an experimental hamster model [74]. LFF571 has been shown to reduce levels of C. difficile toxin production in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels [75]. It is non-absorbed, reaching high intracolonic concentrations [76,77]. A phase I randomized double-blind placebo-controlled dose ranging study evaluated the safety and tolerability of LFF571 in 56 healthy volunteers [76]. Single (25 mg, 100 mg, 400 mg, and 1000 mg) and multiple ascending doses (25 mg, 100 mg, 200 mg every 6 hours for 10 days) were successfully administered without any participants withdrawing due to adverse effects. The drug was generally well tolerated with 7 of 24 subjects (29.2 %) who received LFF571 and 1 of 8 subjects (12.5 %) who received placebo experiencing an adverse effect. The most common adverse effects were diarrhea, abdominal pain, and distension [76]. A phase II multicenter randomized active controlled study recruited 72 adults presenting with initial and recurrent CDI [78]. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was clinical cure at 1–3 days after the end of therapy, defined as resolution or improvement in symptoms with no requirement for additional therapy. In a per-protocol analysis, clinical response rates at the end of treatment were better for LFF571 (90.6 %) than for vancomycin (78.3 %). However, recurrence rates were higher with LFF571 (27 %) than vancomycin (16 %). Overall, this led to similar clinical response rates for LFF571 (56.7 %) and vancomycin (65.0 %).

19. CRS3123 (formerly REP3123) This agent’s mode of action is by inhibition of protein synthesis via methionyl-tRNA synthetase. It is poorly absorbed and has a narrow spectrum of activity [79]. In a hamster model the drug was reported to inhibit toxin and spore formation [80]. CRS3123 exhibits potent in vitro activity against Gram-positive bacteria including C. difficile, but little activity against Gramnegative bacteria. It also has little activity against several groups of indigenous gut flora including Bifidobacterium and Lactobacillus [79]. A Phase I dose ranging study for clinical efficacy and safety was conducted in 40 healthy volunteers [81]. This group was divided into five cohorts of eight subjects each receiving CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1200 mg. Similar rates of adverse effects were reported in 93.3 % (28/30) of the CRS3123-treated subjects and in 90.0 % (9/10) of the placebo-treated subjects [81]. Although found to be poorly absorbed in the animal model (with oral bioavailability in hamsters of <1 %), in humans poorly quantified serum levels of drug and/or active metabolites were detectable 2–3 hours after oral administration [81]. This finding will require more detailed investigation in future studies.

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20. MCB3837/MCB3681

Disclosure of interest

MCB3837 is a water-soluble small molecule prodrug of the active substance MCB3681. This compound is a hybrid fluoroquinolone-oxazolidinone which is being developed as an intravenous preparation. It may be particularly useful for patients presenting with CDI who do not tolerate oral therapy. Such situations may arise in cases of severe diarrhea where gut transit is accelerated, or in cases of ileus. It has potent in vitro activity against Gram-positive bacteria including a wide range of C. difficile strains. It has little activity against the Gram-negative microflora [82]. An in vitro study including 199 diverse isolates demonstrated good activity and no evidence of resistance [83]. A dose ranging phase I study has been conducted in 12 healthy males at a dose of 6 mg/kg for five days, which showed limited impact on the fecal microbiota [84]. Safety data suggests this drug is well tolerated. However, several volunteers experienced mild phlebitis and there were some transient increases in liver enzymes. Phase II studies of this agent are currently being planned.

The authors have not supplied their declaration of competing interest.

21. MGB-BP-3 This compound binds selectively to A-T or G-C rich sequences within the minor groove of bacterial DNA, interfering with transcription factors. A double-blind placebo-controlled Phase I study of single and incrementally increasing doses of orally administered MGB-BP-3 included 16 healthy subjects. Dose levels of MGB-BP-3 were increased from 250 mg to 2,000 mg. In the multiple dose part of the study 250 mg, 500 mg, and 1000 mg doses of MGB-BP-3 were given twice daily for 10 days. The Phase I study showed that MGB-BP-3 was well tolerated with no serious adverse effects being observed. The trial also examined the effect of MGB-BP-3 on normal gut flora, finding a relative increase in proteobacteria in volunteer stool samples, the significance of which is uncertain. Although this agent has been shown to have good in vitro activity against a range of C. difficile isolates, it is also active against a wide range of other Gram-positive bacteria which may be detrimental to the indigenous flora [85,86]. A phase II study is currently being planned.

22. Conclusion Treatment of CDI and in particular rCDI is challenging and there remains an unmet clinical need despite the introduction of newer treatments such as fidaxomicin and bezlotoxumab. FMT has been shown to be highly efficacious but is not commonly used due to access and regulatory barriers in some geographical areas, as well as uncertainty over long-term safety. There are a number of antimicrobials currently under development, which appear to have little effect on the indigenous microflora and may result in significantly reduced rates of recurrence. These agents will be welcome additions to the current armamentarium.

References [1] Goldenberg SD. Faceal microbiota transplantation for recurrent Clostridium difficile infection and beyond: risks and regulation. J Hosp Infect 2016;92:115–6. [2] Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302–7. [3] 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;364:422–31. [4] 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 United State of America: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12: 281–9. [5] McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769–75. [6] Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Hernandez AV, et al. Risk factors for recurrent clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2015;36:452–60. [7] O’Horo JC, Jindai K, Kunzer B, Safdar N. Treatment of recurrent Clostridium difficile infection: a systematic review. Infection 2014;42:43–59. [8] Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect 2015;21:164–70. [9] Shivashankar R, Khanna S, Kammer PP, Scott Harmsen W, Zinsmeister AR, Baddour LM, et al. Clinical predictors of recurrent Clostridium difficile infection in out-patients. Aliment Pharmacol Ther 2014;40:518–22. [10] Razik R, Rumman A, Bahreini Z, McGeer A, Nguyen GC. Recurrence of Clostridium difficile infection in patients with inflammatory bowel disease: The RECIDIVISM study. Am J Gastroenterol 2016;111:1141–6. [11] Dupont HL. The search for effective treatment of clostridium difficile infection. N Engl J Med 2011;364:473–5. [12] Baines SD, O’Connor R, Freeman J, Fawley WN, Harmanus C, Mastrantonio P, et al. Emergence of reduced susceptibility to metronidazole in clostridium difficile. J Antimicrob Chemother 2008;62:1046–52. [13] Lynch T, Chong P, Zhang J, Hizon R, Du T, Graham MR, et al. Characterization of a stable, metronidazole-resistant Clostridium difficile clinical isolate. PLoS One 2013;8:e53757. [14] Musher DM, Aslam S, Logan N, Nallacheru S, Bhaila I, Borchert F, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005;40:1586–90. [15] Brown AT, Seifert CF. Effect of treatment variation on outcomes in patients with Clostridium difficile. Am J Med 2014;127:865–70. [16] Goldenberg SD, Brown S, Edwards L, Gnanarajah D, Howard P, Jenkins D, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis 2015;35:251–9. [17] Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May ML, 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;46:479–93. [18] Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20Suppl. 2:1–26.

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H.G. Maxwell-Scott, S.D. Goldenberg / Médecine et maladies infectieuses 48 (2018) 1–9

[19] Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478–98. [20] Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431–55. [21] Louie TJ, Peppe J, Watt CK, Johnson D, Mohammed R, Dow G, et al. Tolevamer, a novel nonanibiotic polymer, compared with vancomycin in the treatment of mild to moderately sever Clostridium difficile-associated diarrhea. Clin Infect Dis 2006;43:411–20. [22] 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;59:345–54. [23] Nerandzic MM, Mullane K, Miller MA, Babakhani F, Donskey CJ. Reduced acquisition and overgrowth of vancomycin-resistant enterococci and candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection. Clin Infect Dis 2012;55(2):S121–6. [24] Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect 2009;58:403–10. [25] Credito KL, Appelbaum PC. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob Agents Chemother 2004;48:4430–4. [26] Tannock G, Munro K, Taylor C, Lawley B, Young W, Byrne B, et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiol 2010;156(11):3354–9. [27] Louie TJ, Cannon K, Byrne B, Emery J, Ward L, Eyben M, et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis 2012;55(2):S132–42. [28] Louie TJ, Emery J, Krulicki W, Byrne B, Mah M. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C Difficile infection. Antimicrob Agents Chemother 2009;53:261–3. [29] Babakhani F, Gomez A, Robert N, Sears P. Postantibiotic effect of fidaxomicin and its major metabolite (OP-1118) against C. difficile. Antimicrob Agents Chemother 2011;55:4427–9. [30] Babakhani F, Gomez A, Robert N, Sears P. Postantibiotic effect of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile. Antimicrob Agents Chemother 2011;55:4427–9. [31] Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis 2012;55(2):S162–9. [32] Allen CA, Babakhani F, Sears P, Nguyen L, Sorg JA. Both fidaxomicin and vancomycin inhibit outgrowth of Clostridium difficile spores. Antimicrob Agents Chemother 2012;57:664–7. [33] Babakhani F, Bouillaut L, Sears P, Sims C, Gomez A, Sonenshein AL. Fidaxomicin inhibits toxin production in Clostridium difficile. J Antimicrob Chemother 2013;68:515–22. [34] Thabit AK, Alam MJ, Khaleduzzaman M, Garey KW, Nicolau DP. 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. [35] Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother 2009;53:223–8. [36] Mancano MA. Vigabatrin-Induced encephalopathy; fidaxomicin hypersensitivity reactions; vemurafenib-induced DRESS; severe alkalosis and hypokalemia with stanozolol misuse; isotretinoin-associated lip abscess; eltrombopag-associated hyperpigmentation. Hosp Pharm 2014;49:420–4. [37] Eyre DW, Babakhani F, Griffiths D, Seddon J, Del Ojo Elias C, Gorbach SL, et al. Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile. J Infect Dis 2014;209:1446–51.

[38] Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012;55(2):S93–103. [39] Mullane KM, Miller MA, Weiss K, Lentnek A, Golan Y, Sears PS, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis 2011;53:440–7. [40] Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis 2012;55(2):S154–61. [41] Cornely OA, Miller MA, Fantin B, Mullane K, Kean Y, Gorbach S. Resolution of Clostridium difficile-associated diarrhea in patients with cancer treated with fidaxomicin or vancomycin. J Clin Oncol 2013;31(19):2493–9. [42] Esmaily-Fard A, Tverdek FP, Crowther DM, Ghantoji SS, Adachi JA, Chemaly RF. The use of fidaxomicin for treatment of relapsed Clostridium difficile infections in patients with cancer. Pharmacother 2014;34(11):1220–5. [43] Guery B, Menichetti F, Veli-Jukka A, Adomakkoh N, Maria Aguado J, Bisnauthsing K, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection (EXTEND): a randomised, controlled, open-label study in an older patient population. Lancet Infect Dis 2017 [In press]. [44] Vargo CA, Bauer KA, Mangino JE, Johnston JE, Goff DA. An antimicrobial stewardship program’s real-world experience with fidaxomicin for treatment of Clostridium difficile infection: a case series. Pharmacother 2014;34:901–9. [45] Gallagher JC, Reilly JP, Navalkele B, Downham G, Haynes K, Trivedi M. Clinical and economic benefits of fidaxomicin compared to vancomycin for Clostridium difficile infection. Antimicrob Agents Chemother 2015;59:7007–10. [46] Cornely OA, Nathwani D, Ivanescu C, Odufowora-Sita O, Retsa P, Odeyemi IA. Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: a meta-analysis and indirect treatment comparison. J Antimicrob Chemother 2014;69:2892–900. [47] Penziner S, Dubrovskaya Y, Press R, Safdar A. Fidaxomicin therapy in critically ill patients with Clostridium difficile infection. Antimicrob Agents Chemother 2015;59:1776–81. [48] Fehér C, Mú˜nez Rubio E, Merino Amador P, Delgado-Iribarren GarciaCampero A, Salavert M, Merino E, et al. The efficacy of fidaxomicin in the treatment of Clostridium difficile infection in a real-world clinical setting: a Spanish multi-centre retrospective cohort. Eur J Clin Microbiol Infect Dis 2017;36:295–303. [49] Biswas JS, Patel A, Otter JA, Wade P, Newsholme W, van Kleef E, et al. Reduction in Clostridium difficile environmental contamination by hospitalized patients treated with fidaxomicin. J Hosp Infect 2015;90:267–70. [50] Johnson S, Homann SR, Bettin KM, Quick JN, Clabots CR, Peterson LR, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med 1992;117:297–302. [51] Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis 2016;63:651–3. [52] Carignan A, Poulin S, Martin P, Labbé AC, Valiquette L, Al-Bachari H, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol 2016;111:1834–40. [53] Mullane KM, Adachi J, Dubberke E, Alexander B, Broyde N, Sears P. Outcomes of deflect-1: a multicenter, blinded, randomized clinical trial of fidaxomicin (FDX) vs. placebo (PLC) for prophylaxis of Clostridium difficile associated diarrhea (CDAD) in subjects undergoing hematopoietic stem cell transplantation (HSCT). Biol Blood Marrow Transplant 2016;22:S171. [54] Bassères E, Endres BT, Khaleduzzaman M, Miraftabi F, Alam MJ, Vickers RJ, et al. Impact on toxin production and cell morphology in Clostridium

H.G. Maxwell-Scott, S.D. Goldenberg / Médecine et maladies infectieuses 48 (2018) 1–9

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64]

[65]

[66] [67] [68] [69]

[70]

difficile by ridinilazole (SMT19969), a novel treatment for C. Difficile infection. J Antimicrob Chemother 2016;71:1245–51. Goldstein EJ, Citron DM, Tyrrell KL. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against 162 strains from 35 less frequently recovered intestinal clostridium species: implications for Clostridium difficile recurrence. Antimicrob Agents Chemother 2014;58:1187–91. Corbett D, Wise A, Birchall S, Warn P, Baines SD, Crowther G, et al. In vitro susceptibility of clostridium difficile to SMT19969 and comparators, as well as the killing kinetics and post-antibiotic effects of SMT19969 and comparators against C. difficile. J Antimicrob Chemother 2015;70:1751–6. Vickers R, Robinson N, Best E, Echols R, Tillotson G, Wilcox M. A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections. BMC Infect Dis 2015;15:759. Vickers RJ, Tillotson GS, Nathan R, Hazan S, Pullman J, Lucasti C, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis 2017;17:735–44. Goldenberg SD. Expanding the armamentarium for the treatment of Clostridium difficile infection. Lancet Infect Dis 2017;17:678–80. Locher HH, Caspers P, Bruyère T, Schroeder S, Pfaff P, Knezevic A, et al. Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother 2014;58:901–8. Locher HH, Seiler P, Chen X, Schroeder S, Pfaff P, Enderlin M, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother 2014;58:892–900. Chilton CH, Crowther GS, Baines SD, Todhunter SL, Freeman J, Locher HH, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother 2014;69:697–705. Caspers P, Locher HH, Pfaff P, Diggelmann S, Rueedi G, Bur D, et al. Different resistance mechanisms for cadazolid and linezolid in C. difficile found by whole genome sequencing analysis. Antimicrob Agents Chemother 2017;61:e00384–390. Gehin M, Desnica B, Dingemanse J. Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection. Int J Antimicrob Agents 2015;46:576–81. Louie T, Nord CE, Talbot GH, Wilcox M, Gerding DN, Buitrago M, et al. A multicenter, double-blind, randomized, phase 2 study evaluating the novel antibiotic, cadazolid, in patients with Clostridium difficile infection. Antimicrob Agents Chemother 2015;59:6266–73. [Accessed on August 15] https://clinicaltrials.gov/ct2/show/study/ NCT01987895. [Accessed on August 15] https://clinicaltrials.gov/ct2/show/NCT01983683. [Accessed on August 10] https://www1.actelion.com/en-rebranded/media/ media-releases.page??newsId=2111437. Mascio CT, Mortin LI, Howland KT, Van Praagh AD, Zhang S, Arya A, et al. In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. Antimicrob Agents Chemother 2012;56:5023–30. Lee CH, Patino H, Stevens C, Rege S, Chesnel L, Louie T, et al. Surotomycin versus vancomycin for Clostridium difficile infection: phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother 2016;71:2964–71.

9

[71] Boix V, Fedorak RN, Mullane KM, Pesant Y, Stoutenburgh U, Jin M, et al. Primary outcomes from a phase 3, randomised, double-blind, activecontrolled trial of surotomycin in subjects with Clostridium difficile infection. Open Forum Infect Dis 2017:4: ofw275. [72] Leeds JA, Sachdeva M, Mullin S, Dzink-Fox J, Lamarche MJ. Mechanism of action of, and mechanism of reduced susceptibility to the novel antiClostridium difficile compound LFF571. Antimicrob Agents Chemother 2012;56:4463–5. [73] Citron DM, Tyrrell KL, Merriam CV, Goldstein EJ. Comparative in vitro activities of LFF571 against Clostridium difficile and 630 other intestinal strains of aerobic and anaerobic bacteria. Antimicrob Agents Chemother 2012;56:2493–503. [74] Trzasko A, Leeds JA, Praestgaard J, Lamarche MJ, McKenney D. Efficacy of LFF571 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother 2012;56:4459–62. [75] Sachdeva M, Leeds JA. Subinhibitory concentrations of LFF571 reduce toxin production by Clostridium difficile. Antimicrob Agents Chemother 2015;59:1252–7. [76] Ting L, Praestgaard J, Grunenberg N, Yang JC, Leeds JA, Pertel P. A first-in-human, randomized, double-blind, placebo-controlled, singleand multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob Agents Chemother 2012;56:5946–51. [77] Bhansali SG, Mullane K, Ting LS, Leeds JA, Dabovic K, Praestgaard J, et al. Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections. Antimicrob Agents Chemother 2015;59:1441–5. [78] Mullane K, Lee C, Bressler A, Buitrago M, Weiss K, Dabovic K, et al. Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections. Antimicrob Agents Chemother 2015;59:1435–40. [79] Citron DM, Warren YA, Tyrrell KL, Merriam V, Goldstein EJ. Comparative in vitro activity of REP3123 against clostridium difficile and other anaerobic intestinal bacteria. J Antimicrob Chemother 2009;63:972–6. [80] Ochsner UA, Bell SJ, O’Leary AL, Hoang T, Stone KC, Young CL, et al. Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile, and in vivo efficacy in a hamster gastrointestinal infection model. J Antimicrob Chemother 2009;63:964–71. [81] Nayak SU, Griffiss JM, Blumer J, O’Riordan MA, Gray W, McKenzie R, et al. Safety, tolerability, systemic exposure and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile infections, in a phase I study. Antimicrob Agents Chemother 2017;61:e02761–2816. [82] Rashid MU, Dalhoff A, Weintraub A, Nord CE. In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe 2014;28:216–9. [83] Freeman J, Pilling S, Vernon J, Wilcox MH. In vitro activities of MCB3681 and eight comparators against Clostridium difficile isolates with known ribotypes and diverse geographical spread. Antimicrob Agents Chemother 2017;61:e02077–2116. [84] Dalhoff A, Rashid MU, Kapsner T, Panagiotidis G, Weintraub A, Nord CE. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect 2015;21:767.e1–4. [85] [Accessed on October 13] https://clinicaltrials.gov/ct2/show/NCT02518607. [86] Ravic M, Firmin D, Sahgal O, van den Berg F, Suckling C, Hunter IS. A single-centre, double-blind, placebo-controlled study in healthy men to assess the safety and tolerability of single and repeated ascending doses of MGB-BP-3, a new class of antibacterial agent. Boston: ASM Microbe; 2016 [Abstract 524].