Novel dosing regimens for tiacumicin compounds

Abstract

To provide tiacumicin compounds and dosage regimen for use in the oral treatment of Clostridium difficile infections (CDI) or Clostridium difficile-associated disease (CDAD).SOLUTION: The invention provides one or more tiacumicin compounds, a stereo-isomer thereof, a polymorph thereof or a pharmaceutically acceptable solvate thereof for use in the oral treatment of CDI or CDAD in a patient according to a dosage regimen comprising the steps of: administering to the patient in an initial course of treatment 200 mg of the tiacumicin compound twice a day; monitoring the efficacy of the initial course of treatment in the patient by means of monitoring changes of one or more indicators of CDI or CDAD; assessing whether there is a positive change of the one or more of the indicators; and switching to an intermittent course of treatment by administering to the patient 200 mg of the tiacumicin compound every other day if the one or more of the indicators of CDI or CDAD are positively changed. The invention also provides the use of tiacumicin compounds to reduce recurrence in a patient suffering from CDI or CDAD.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel dosing regimens of tiacumicin compounds, stereoisomers thereof, polymorphs thereof, or pharmaceutically acceptable solvates thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient, to the use of the novel dosing regimens for the oral treatment of CDI or CDAD, and to the reduction of recurrence of CDI or CDAD in a patient after completion of treatment. [Background technology]

[0002] Tiacumicin compounds, particularly fidaxomicin, are indicated for the treatment and prevention of recurrence of Clostridium difficile infection (CDI), also known as Clostridium difficile-associated disease (CDAD). CDI represents a significant burden to healthcare facilities worldwide (Wiegand PN, Nathwani D, Wilcox MH et al. in J. Hosp. Infect of 10 April 2012; Ghantoji SS, Sail, K. Lairson DR (2010) in J. Hosp. Infect. 74: 309-318). This infection, usually caused by changes in the composition and function of the intestinal flora after antimicrobial use, is called antibiotic-associated diarrhea (AAD).Clostridium difficile infection (CDI), also known as C. difficile-associated disease (CDAD), refers to a wide range of diarrheal illnesses caused by toxins produced by this microorganism, including cases of severe colitis with or without pseudomembranes.

[0003] The development of AAD is highly variable and influenced by several factors, including nosocomial outbreaks, antibiotic prescribing patterns, and individual susceptibility. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics develop AAD. Most importantly, approximately twice as many patients are asymptomatic carriers. Risk factors include immunocompromised states, advanced age, abdominal surgery, comorbidities, type and prolonged use of antibiotics, reduced gastric acidity, and length of hospitalization. For example, the infection rate for Clostridium difficile has been reported to be approximately 10% after 2 weeks of hospitalization but may reach 50% after 4 weeks or more (McFarland LV. Epidemiology, risk factors, and treatments for antibiotic-associated diarrhea. Dig Dis 1998;16:292-307). Although all groups of antibiotics can cause AAD, those with broad spectrum activity, particularly cephalosporins, fluoroquinolones, extended-coverage penicillins, and clindamycin, are the most common causes (Wistrom J, Norrby SR, Myhre E, et al. Frequency of antibiotic-associated diarrhea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47:43-50). Treatment options are limited and are associated with high rates of recurrence.

[0004] Tiacumicin compounds are naturally occurring compounds with antibiotic activity that can be obtained by culturing various microorganisms belonging to the family Actinoplanes (particularly the genus Dactylosporangium aurantiacum, subspecies hamdenensis) in an appropriate nutrient medium at an appropriate temperature and isolating compounds with antibiotic activity against various microorganisms (Tiacumicins A-F; U.S. Pat. No. 4,918,174). Tiacumicins B and C, in particular, were found to have in vitro antibiotic activity against several Gram-positive bacteria, including strains that were resistant to the therapeutic antibiotics in use at the time. U.S. Patent No. 5,583,115 discloses that dialkyl tiacumicin compounds, which are derivatives of the above-mentioned tiacumicin compounds A to F, have been found to have in vitro activity against various bacterial pathogens, particularly against Clostridium species. U.S. Patent No. 5,767,096 discloses bromotiacumicin compounds, also derivatives of tiacumicin compounds A-F, which have been found to have in vitro activity against some bacterial pathogens, particularly Clostridium species.

[0005] From a chemical standpoint, Tiacumicins share an 18-membered macrocyclic ring glycosidically linked to one or two optionally substituted sugar molecules, as shown in Formula I below (U.S. Pat. No. 4,918,174 and WO 2004 / 014295). [ka] WO2004 / 014295 describes a substantially pure R-tiacumicin obtained by submerged aerobic fermentation of Dactylosporangium aurantiacum hamdenensis.

[0006] WO2006 / 085838 discloses pharmaceutical compositions containing R-Tiacumicins, in particular R-Tiacumicin B (also known as Fidaxomicin), which contains an R-hydroxy group at C19 and exhibits surprisingly lower MIC values ​​(MIC means minimum inhibitory concentration) than the optically pure S-isomer of Tiacumicin B and than other Tiacumicin-related compounds when tested in vitro against Clostridium species.

[0007] In vitro BCS (Biological Classification System) studies have shown that fidaxomicin is a BCS Class IV compound (poorly soluble, poorly permeable). When administered orally, fidaxomicin is poorly absorbed from the intestinal tract and therefore has a low incidence of associated systemic side effects. Tablets containing 200 mg of fidaxomicin are commercially available in Europe (under the trademark Dificlir) and in the United States (under the trademark Dificin). Fidaxomicin is indicated for the treatment and prevention of recurrence of Clostridium difficile infection (CDI), also known as Clostridium difficile-associated disease (CDAD). In two phase III randomized, double-blind clinical trials, fidaxomicin was non-inferior to vancomycin in achieving initial clinical cure of CDI, but was superior in reducing recurrences and achieving a sustained clinical response (Crook et al. (2012) in Clin. Infect. Dis. 55(Suppl 2):S93-103).

[0008] In a Phase III trial, the risk of failure of fidaxomicin or vancomycin treatment doubled for each treatment day less than 10 days (T. Louie et al. Poster presented at 22 ndEuropean Congress of Clinical Microbiology & Infectious Diseases, March 31 - April 3, 2012, London). Fidaxomicin has a relatively low effect on the intestinal flora, resulting in better bacterial recovery over the course of long-term treatment, and thus a reduced risk of CDI recurrence (TJLouie et al. (2012) in Clin. Infect. Dis. 55(S2) S132-142; Tannock in Microbiology (2010), 156, 3354-3359 (Phase II trials)).

[0009] Management of Clostridium difficile infection (CDI) is consequently complicated by a high recurrence rate, with over 50% of second episodes being due to relapse (RCDI = recurrent CDI). Guidelines recommend managing multiple relapses with vancomycin tapering. No clear recommendations are available for patients in whom this approach fails. In a recent case series (Soriano et al. in Exp Rev Antiinf Ther 2013;11:767-776), patients with multiple RCDIs refractory to vancomycin tapering therapy received either fidaxomicin 200 mg twice daily for 10 days (referred to as FID-TX) or CDI treatment followed by repeat CDI treatment, either a 10-day chase with fidaxomicin (referred to as FID-CH) or a taper of 200 mg daily for 7 days followed by 200 mg every other day for 7 to 26 days (referred to as FID-TP). Demographic information, CDI history, treatment outcome, and symptom-free interval (SFI) were collected from patient records. Treatment was considered successful if symptoms resolved by the end of treatment and no additional antibiotics were required. Recurrent CDI (RCDI) was defined as the development of CDI symptoms after successful treatment of a previous episode. Fourteen patients received 18 treatment courses of fidaxomicin for RCDI (mean age 60 years, mean 4.6 previous CDI episodes, mean 2.3 previous vancomycin tapering courses). All 18 courses resulted in successful treatment (three courses of FID-TX, eight courses of FID-CH, and seven courses of FID-TP). Two RCDI episodes occurred during the three courses of FID-TX (66%). Excluding RCDI due to antimicrobial exposure, two RCDI cases (25%) were observed after eight courses of FID-CH, and no RCDI cases were observed after seven courses of FID-TP. The mean SFI after vancomycin tapering was 37 days. The mean SFI after FID-TX, FID-CH, and FID-TP was 73, 240, and 150 days, respectively. Patients with RCDI who had failed multiple vancomycin tapers experienced symptom resolution after fidaxomicin therapy.All three regimens resulted in a longer SFI compared with vancomycin tapering. No patients experienced RCDI after FID-TP. FID-CH had the longest SFI, but the follow-up time with FID-TP was shorter considering the more recent adoption of this regimen. These results suggest the utility of using fidaxomicin to treat RCDI (MM Soriano et al. Abstract 42591; presentation No. 1410; IDWeek, 5 October 2013). The currently recommended treatment regimen for adults and elderly people (65 years and older) is 200 mg twice daily (q12h) for 10 days.

[0010] Several dosing regimens have already been tested for their activity in in vitro intestinal models; for example, a validated CDI model was used to investigate the efficacy of a long-pulse (Model A: 200 mg twice daily for 20 days) versus a short-pulse (Model B: 200 mg twice daily for 5 days on, 5 days off, and 200 mg twice daily for 5 days) course of fidaxomicin. Results are available for this model (CH Chilton et al. (2013) in J. Antimicrobial Chemotherapy Advance Access Sept 2013 and CH Chilton et al., abstract 23 rd European Congress of Clinical Microbiology & Infectious Disease, April 27-30, 2013, Berlin). Various fidaxomicin dosing regimens have been tested in in vitro human intestinal models simulating CDI or CDAD, but it is unclear whether these dosing regimens would be effective when administered to patients as required by the present invention (CH Chilton et al (2014) in J. Antimicrobial Chemotherapy, 70:2598-2607 and CH Chilton (14 May 2014), poster presentation P0797).

[0011] In addition, a comparison was made between two other models: Model A, which consists of 200 mg fidaxomicin twice daily for 5 days, followed by a 5-day break, and then again 200 mg fidaxomicin once daily for another 10 days; and Model B, which consists of 200 mg fidaxomicin twice daily for 5 days, followed by one dose of 200 mg fidaxomicin every other day (Poster P0797, presented at the poster session on May 11, 2014, at the ECCMID Congress in Barcelona). None of the above-cited dosing regimens solved the problem of high recurrence of CDI or CDAD, which is defined in this study as the recurrence of >3 diarrheal stools in a 24-hour period within 30 days of the end of treatment (EOT), the presence of Clostridium difficile toxin A or toxin B, or both, in the stool, and the need for retreatment for CDI. There are various indicators of CDI or CDAD that can be used to test positive, either alone or in combination, to diagnose C. difficile infection. Suitable indicators include stool consistency, frequency of diarrhea, presence of C. difficile toxin A (TcdA toxin) or toxin B (TcdB toxin), presence of C. difficile toxin A gene (tcdA) or B gene (tcdB), and presence of C. difficile surface antigen (GDH = glutamate dehydrogenase). An accepted model for those skilled in the art is the Bristol Stool Form Scale published by SJ Lewis et al. in the Scandinavian Journal of Gastroenterology, 1997, Vol. 32, No. 9, pages 920-924. In Table 1 of this publication, seven types of the Bristol Stool Form Scale are defined, with Type 7 being watery stool and Type 1 being discrete hard lumps.

[0012] [Table 1]

[0013] It is extremely important to apply the correct dosing regimen to patients to achieve the treatment goal. Emphasis should be placed on the route of administration, formulation composition, unit dose, administration frequency, dosage amount, and treatment duration. However, there remains a need to provide a flexible dosing regimen that can be adapted according to changes in a certain indicator of CDI or CDAD or the reduction of a certain indicator of the intestinal flora, in order to ensure the best possible treatment for each patient and reduce the recurrence of CDI or CDAD in said patient to the lowest level after completion of treatment. Summary of the Invention

[0014] After extensive investigation, the inventors have now discovered one or more of a tiacumicin compound, its stereoisomers, polymorphs, or pharmaceutically acceptable solvates thereof, for use in the oral treatment of a patient suffering from Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) using a dosing regimen comprising: (1) administering 200 mg of a tiacumicin compound twice daily to the patient during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) switching to an intermittent treatment course in which 200 mg of the tiacumicin compound is administered to the patient every other day if there is a positive change in one or more indicators of CDI or CDAD. Furthermore, the present invention provides uses of a tiacumicin compound for reducing recurrence in a patient suffering from CDI or CDAD, as well as methods of reducing recurrence. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention relates to a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of the tiacumicin compound to the patient twice daily during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent course of treatment in which 200 mg of the tiacumicin compound is administered to the patient every other day. The Tiacumicin compounds according to the present invention have an 18-membered macrocyclic glycoside structure and are compounds disclosed in U.S. Pat. Nos. 4,918,174, 5,583,115, 5,767,096, and Chinese Patent Applications Nos. 201010526416.9 and 201110104051.5, which are incorporated herein by reference.

[0016] Preferred tiacumicin compounds are selected from the group consisting of tiacumicin A, tiacumicin B, and their analogs (dialkyltiacumicins and bromotiacumicins), tiacumicin C, tiacumicin D, tiacumicin E, tiacumicin F, and lipiarmycin. All tiacumicin compounds have in common that they are insoluble or practically insoluble in water, but more preferably the active ingredient is lipiarmycin or tiacumicin B, or a stereoisomer or polymorph thereof. An even more preferred tiacumicin compound is R-tiacumicin B (also known as fidaxomicin, OPT-80, or PAR-101).

[0017] R-Tiacumicin B is fidaxomicin (3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-l-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-ll(S)-ethyl- 8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one or It is also known as oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-l-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(lR)-1-hydroxyethyl]-9,13,15-trimethyl-,(3E,5E,8S,9E,11S,12R,13E,15E,18S)). It is a narrow-spectrum compound, active against Clostridium difficile and most strains of staphylococci and enterococci, but with negligible activity against gram-negative bacteria and fungi. It is obtained by fermentation of Dactylosporangium auranticum and has the following formula (II):

[0018] [ka] Corresponds to.

[0019] Accordingly, another embodiment of the present invention relates to a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient by a dosing regimen comprising: (1) administering 200 mg of a tiacumicin compound to the patient twice daily during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent course of treatment in which 200 mg of the tiacumicin compound is administered to the patient every other day, wherein the tiacumicin compound is fidaxomicin (R-tiacumicin B).

[0020] The phrase "stereoisomer thereof" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Examples of stereoisomers include enantiomers and diastereomers. The term "enantiomer" refers to one of a pair of molecular species that are non-superimposable mirror images of each other. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric species, which composition lacks optical activity. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. As used herein, the isomeric descriptors "R" and "S" are used to indicate the configuration of atoms relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure & Applied Chemistry 68: 2193-2222). The term "polymorph thereof" describes any alternative crystalline form having different physical properties as a result of different arrangements of molecules within the crystal lattice. More specifically, it includes, for example, the polymorphs disclosed in WO 2008 / 091554. The term "pharmaceutically acceptable solvate thereof" refers to any pharmaceutically acceptable solvate that is administered (directly or indirectly) to a patient to provide the Tiacumicin compound. Preferably, the solvate is a hydrate, a solvate with an alcohol such as methanol, ethanol, propanol, or isopropanol, a solvate with an ester such as ethyl acetate, a solvate with an ether such as methyl ether, ethyl ether, or THF (tetrahydrofuran), or a solvate with DMF (dimethylformamide), of which a hydrate or a solvate with an alcohol such as ethanol is more preferred. The solvent for forming the solvate is preferably a pharmaceutically acceptable solvent. CDI means Clostridium difficile infection, and CDAD means Clostridium difficile-associated disease or diarrhea. Both terms have the same meaning and are interchangeable. When reference is made to CDI in this invention, this also includes CDAD, and vice versa. The term "patient" means any human suffering from CDI or CDAD.

[0021] The disease activity of C. difficile infection can be monitored by various indicators. Suitable indicators include stool consistency, frequency of diarrhea, the presence of C. difficile toxin A (TcdA toxin) or toxin B (TcdB toxin), the co-presence of C. difficile toxin A (TcdA toxin) and toxin B (TcdB toxin), the presence of C. difficile toxin B gene (tcdB) or C. difficile toxin A gene (tcdA), the co-presence of C. difficile toxin B gene (tcdB) and C. difficile toxin A gene (tcdA), and the presence of C. difficile surface antigen (GDH = glutamate dehydrogenase), and possibly inflammatory biomarkers, such as fecal lactoferrin (detected by enzyme immunoassay (EIA) from, for example, Hycultbiotech), calprotectin (detected by, for example, Hycultbiotech or BIOHIT). These include CRP (detected by enzyme immunoassay (EIA) from Novex), fecal IL-8 mRNA (detected by qRT-PCR; Feghaly et al., 2013:57, Clinical Infection Diseases), and fecal CXCL-5 mRNA (detected by qRT-PCR; Feghaly et al., 2013:57, Clinical Infection Diseases). The various indicators can be used alone or in combination with one another to determine the patient's condition.

[0022] In the present invention, preferred indicators for monitoring CDI or CDAD are selected from the group consisting of (a) diarrhea frequency, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH). These indicators can be used alone or in combination with one or more of the selected indicators to monitor CDI or CDAD, respectively.

[0023] In the present invention, the phrase "positively changed" or "positive change" refers to the fact that a specific indicator of CDI or CDAD is compared at the start of treatment and during the initial treatment course to determine whether the initial treatment course is effective for treating CDI or CDAD. Effective treatment results in an improved value of the indicator (i.e., a positive change in the indicator or a positive change in the indicator), which means that the value of the indicator decreases during the initial treatment course, making it possible to switch the patient to an intermittent treatment course. The meaning of a positive change is explained below for each preferred indicator.

[0024] The phrase "favorably altered" in the present invention refers to the fact that certain indicators of the intestinal flora are compared at the start of treatment and during the course of intermittent treatment to determine whether the intestinal flora has recovered and whether the intermittent treatment can be discontinued. "Favorably altered" in the present invention refers to an increase in the population of microorganisms that support colonization resistance against CDI (e.g., Bacteroidetes and Firmicutes) and a decrease in the population of microorganisms that are adverse to colonization resistance against CDI (e.g., Proteobacteria).

[0025] Another embodiment of the present invention includes the steps of: (1) administering 200 mg of a tiacumicin compound twice daily to a patient during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring a change in one or more indicators of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD); (3) assessing whether there is a positive change in one or more of the indicators; and (4) administering 200 mg of a tiacumicin compound every other day to the patient if there is a positive change in one or more of the indicators of CDI or CDAD. and optionally switching to an intermittent treatment course, wherein the indicators of CDI or CDAD are selected from the group consisting of: (a) frequency of diarrhea, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH). Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen of the present invention, wherein an indicator of CDI or CDAD is frequency of diarrhea.

[0026] The frequency of diarrhea or unformed bowel movement (UBM) is a suitable indicator for monitoring the symptomatic improvement of CDI or CDAD. For example, a positive change in the indicator is a reduction in the frequency of diarrhea to less than 4 UMB per day for two consecutive days. In a preferred embodiment of the present invention, the frequency of diarrhea is reduced to less than 3 UMB per day for two consecutive days. The frequency of UMB or diarrhea is detected by observation through the patient's notes or bowel diary.

[0027] Another embodiment of the present invention is a tiacumicin compound, its stereoisomer, its polymorph, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient using a dosing regimen of the present invention, wherein the indicator of CDI or CDAD is stool consistency. An accepted model for those skilled in the art is the Bristol Stool Form Scale published by S.J. Lewis et al. in the Scandinavian Journal of Gastroenterology, Vol. 32, No. 9, pages 920-924, 1997. Table 1 of this publication defines seven types of Bristol Stool Form Scale, with Type 7 being watery stool and Type 1 being discrete, hard lumps. In the present invention, a positive change in indicator is a change in stool consistency from Type 7 or Type 6 to Type 4 or below Type 4 according to the Bristol Stool Form Scale. In one preferred embodiment of the present invention, stool consistency shows an improvement from Type 7 or Type 6 to Type 4 on the Bristol Stool Form Scale.

[0028] Another embodiment of the present invention is a tiacumicin compound, its stereoisomer, its polymorph, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of a patient with Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) using a dosing regimen of the present invention, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B (TcdB). During infection, Clostridium difficile produces two important virulence determinants, toxin A (TcdA) and toxin B (TcdB). Therefore, toxin B and toxin A (TcdA) are important indicators of CDI. When an initial treatment course using the dosing regimen of the present invention is effective in treating CDI or CDAD, TcdB and / or TcdA toxins are negative in a qualitative test, or when quantitative assays are used, levels of TcdB and / or TcdA toxins are confirmed to be below the lower limit of detection (LLOD). A preferred embodiment of the Tiacumicin compounds for use in the present invention is the absence of Clostridium difficile toxin B (TcdB toxin). The presence of TcdA and / or TcdB can be determined by enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunosorbent assay (EIA). ELISA and EIA are interchangeable terms. Suitable EIA assays for determining the absence of CDI are the Clostridium difficile TOX A / B II test (TechLab) or the Clostridium difficile TOX-B test (TechLab).

[0029] Another embodiment of the present invention is a tiacumicin compound, its stereoisomer, its polymorph, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of a patient with Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) using a dosing regimen of the present invention, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B gene (tcdB) or Clostridium difficile toxin A gene (tcdA). Effective treatment of CDI or CDAD with a dosing regimen of the present invention is confirmed by the absence of tcdB and / or tcdA when tested with a nucleic acid amplification test, or by the presence of tcdB and / or tcdA levels below the lower limit of detection (LLOD) when a quantitative assay is used. A preferred embodiment of the tiacumicin compound for use in the present invention is the absence of tcdB. A suitable assay for determining the absence of tcdA and / or tcdB is the Xpert C. Difficile assay from Cepheid.

[0030] Another embodiment of the present invention is a tiacumicin compound, its stereoisomer, its polymorph, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of a patient with Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) using a dosing regimen of the present invention, wherein the indicator of CDI or CDAD is Clostridium difficile surface antigen (GDH = glutamic acid dehydrogenase). When an initial course of treatment with a dosing regimen of the present invention is effective in treating CDI or CDAD, the GDH toxin is absent in a qualitative test, or, when using a quantitative assay, GDH levels are below the lower limit of detection (LLOD). A preferred embodiment of the tiacumicin compound for use in the present invention is the absence of GDH. A suitable assay for determining the absence of GDH is, for example, the EIA designated Clostridium difficile CHEK 60, manufactured by TechLab.

[0031] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which the patient is administered 200 mg of fidaxomicin every other day.

[0032] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which the patient is administered 200 mg of fidaxomicin every other day, wherein the stool consistency shows an improvement from Type 7 or Type 6 to Type 4 according to the Bristol Stool Form Scale.

[0033] Another embodiment of the present invention is a tiacumicin compound, its stereoisomer, polymorph, or pharmaceutically acceptable solvate thereof, absent Clostridium difficile toxin B (TcdB) and Clostridium difficile toxin A (TcdA), for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which the patient is administered 200 mg of fidaxomicin every other day.

[0034] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, which is free of Clostridium difficile toxin B (TcdB), for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of fidaxomicin is administered to the patient every other day.

[0035] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, absent the Clostridium difficile toxin B gene (tcdB), for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of fidaxomicin is administered to the patient every other day.

[0036] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, which is free of Clostridium difficile surface antigen (GDH), for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin twice daily to the patient during an initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of fidaxomicin is administered to the patient every other day. Suitable indicators for monitoring recovery from CDI or CDAD may also be urinary metabolic biomarkers, such as a decrease in urinary metabolites associated with Enterobacteriaceae and / or an increase in urinary metabolites associated with urinary obligate anaerobes (e.g., hippuric acid, 4-cresol sulfate). The phrase "initial treatment course" refers to a dosing regimen (or portion of a dosing regimen) used for the initial treatment of a disease. In a preferred embodiment of the invention, the initial treatment course lasts for 3 to 10 days, and even more preferably for 5 days.

[0037] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen of the present invention, further comprising a rest period of 1 to 10 days before the intermittent treatment course. Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen of the present invention, further comprising a rest period of 4 to 6 days before the intermittent treatment course.

[0038] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen of the present invention, further comprising a 5-day rest period before the intermittent treatment course.

[0039] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient according to the dosing regimen of the present invention, wherein the intermittent treatment course lasts from 4 to 40 days, preferably from 10 to 30 days, and even more preferably 20 days. The composition of the gut microbiota in healthy individuals varies depending on the environment, such as diet, age, and geography, but certain microorganisms are commonly found in healthy individuals, such as the phyla Firmicutes (which include the predominant Gram-positive anaerobes, including Clostridia groups XIVa and IV, Lachnospiraceae, and Ruminococcaceae, as well as minor facultative anaerobes such as Enterococci and Lactobacillus) and Bacteroidetes (which include the predominant Gram-negative anaerobes, such as Bacteroides and Prevotella), as well as smaller groups, such as the phyla Actinobacteria (which includes the Bifidobacteria family) and Proteobacteria, such as Enterobacteriaceae.

[0040] The above-mentioned gut flora microorganisms can be considered as an indicator of the recovery of the gut microbiota and ensure that the colonization resistance to CDI is at an appropriate level. To achieve the recovery of the gut microbiota, the populations of Bacterioidetes and Firmicutes need to increase, and the populations of Proteobacteria need to decrease. It is important to achieve an appropriate balance between anaerobic bacteria, for example, between Bacterioidetes and Firmicutes and Proteobacteria, such as Enterobacteriaceae. In another embodiment of the present invention, the intermittent treatment course of the claimed dosing regimen is discontinued when certain indicators known for the restoration of the intestinal flora have changed favorably.

[0041] Accordingly, another embodiment of the present invention relates to a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of a tiacumicin compound twice daily to the patient during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent course of treatment in which 200 mg of the tiacumicin compound is administered to the patient every other day; (5) monitoring one or more indicators of intestinal flora; and (6) discontinuing the intermittent course of treatment if there is a favorable change in one or more of the indicators of intestinal flora.

[0042] A suitable indicator of intestinal flora is the number of Enterobacteriaceae bacteria. Enterobacteriaceae belongs to the Proteobacteria family. In a preferred embodiment of the present invention, the number of Enterobacteriaceae bacteria is reduced by at least 90% compared to the level before the first treatment course. Enterobacteriaceae is a large family of Gram-negative bacteria that includes many more common pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella, and Shigella, as well as many harmless commensal microorganisms. Other pathogens in this family include Proteus, Enterobacter, Serratia, and Citrobacter. A reduction of at least 90% of the number of Enterobacteriaceae bacteria compared to the number before the first treatment indicates a return to normal intestinal function and indicates when to stop treatment.

[0043] Another embodiment of the present invention includes the steps of: (1) administering 200 mg of fidaxomicin twice daily to a patient during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD); (3) assessing whether there is a positive change in one or more of the indicators; and (4) administering fidaxomicin if there is a positive change in one or more of the indicators of CDI or CDAD. A tiacumicin compound, a stereoisomer, a polymorph, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of CDI or CDAD in a patient with a dosing regimen comprising: (1) switching to an intermittent treatment course in which 200 mg of tiacumicin is administered to the patient every other day; (2) monitoring one or more indicators of intestinal flora; and (3) discontinuing the intermittent treatment course if one or more indicators of intestinal flora change favorably, wherein the total number of Enterobacteriaceae bacteria in the intestinal flora is reduced by 90% compared to levels before the first treatment course.

[0044] In a preferred embodiment of the present invention, an intermittent treatment course of a claimed dosing regimen is discontinued when the levels of Bacterioidetes and Firmicutes are 80% of baseline. In another preferred embodiment of the present invention, an intermittent treatment course of a claimed dosing regimen is discontinued when a balance between anaerobes (Bacterioidetes and Firmicutes) and protobacteria is achieved. Fidaxomicin has a narrow spectrum of activity and prolonged antibacterial activity against C. difficile. In addition to the obvious benefit to patients, prevention of recurrence should eliminate the expense of treating further manifestations of C. difficile infection and reduce the rate of person-to-person transmission.

[0045] This is an effective treatment for CDI and is associated with a reduced recurrence rate compared to vancomycin. However, these existing dosing regimens are not optimized for bacterial flora recovery and were selected based on existing practice with vancomycin and metronidazole. However, both vancomycin and metronidazole disrupt the bacterial flora, and therefore recovery cannot begin until treatment is discontinued. The effect of the novel dosing regimen on CDI recurrence is an important factor in the present invention. The effect of the novel dosing regimen on treatment-resistant CDI is also important. The non-inferiority of orally administered fidaxomicin compared with orally administered vancomycin in patients with CDI at 10 days and the superiority shown for the secondary endpoints of relapse rate within 30 days after treatment cessation and sustained cure rate are considered to be of high clinical importance in a previously published phase 3 trial.

[0046] However, despite a significant reduction in recurrence in a Phase III trial from 26% with vancomycin to 14.1% with fidaxomicin (mITT analysis = Modified Intention to Treat Population analysis), recurrent CDI remains a major unmet medical need in this disease area, resulting in significant morbidity and mortality for patients in addition to wider societal and healthcare system costs. The novel dosing regimens of the present invention reduce relapse to less than 10% 30 days after treatment ends, preferably to less than 5% 30 days after treatment ends, and even more preferably to less than 3% 30 days after treatment ends.

[0047] Another embodiment of the present invention is a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, for use in the oral treatment of Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient with a dosing regimen comprising: (1) administering 200 mg of a tiacumicin compound twice daily to the patient during an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of the tiacumicin compound is administered to the patient every other day, wherein the patient experiences a recurrence of CDI or CDAD in less than 10% of cases 30 days after treatment is completed. In a preferred embodiment, less than 5% of patients relapse 30 days after treatment has ended, and in an even more preferred embodiment, less than 3% relapse 30 days after treatment has ended.

[0048] Another embodiment of the present invention relates to the use of a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof for the oral treatment of a patient suffering from CDI or CDAD, wherein the recurrence of CDI or CDAD 30 days after the end of treatment is reduced to less than 10% by a dosing regimen comprising: (1) administering 200 mg of a tiacumicin compound to the patient twice daily during the initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of the tiacumicin compound is administered to the patient every other day.

[0049] Another embodiment of the present invention relates to the use of a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof for oral treatment of a patient suffering from CDI or CDAD, wherein the use of a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof reduces the recurrence of CDI or CDAD to less than 10% 30 days after the end of treatment with a dosing regimen comprising: (1) administering 200 mg of fidaxomicin to the patient twice daily during the initial treatment course; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more indicators of CDI or CDAD, switching to an intermittent treatment course in which the patient is administered 200 mg of fidaxomicin every other day.

[0050] Another embodiment of the present invention is the use of a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof for oral treatment of a patient suffering from CDI or CDAD, reducing the recurrence of CDI or CDAD 30 days after completion of the treatment of the present invention to less than 10%, wherein the indicators of CDI or CDAD are selected from the group consisting of: (a) frequency of diarrhea, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH).

[0051] Another embodiment relates to a method of treating Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) in a patient, comprising: (1) administering 200 mg of a tiacumicin compound to the patient twice daily for an initial course of treatment; (2) monitoring the efficacy of the initial course of treatment in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent course of treatment in which the patient is administered 200 mg of a tiacumicin compound every other day. Another embodiment of the invention is the method of treating CDI or CDAD in a patient of the present invention, wherein the Tiacumicin compound is Fidaxomicin (R-Tiacumicin B). Another embodiment of the present invention is a method of treating CDI or CDAD in a patient of the present invention, wherein the indicators of CDI or CDAD are selected from the group consisting of: (a) frequency of diarrhea, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH). Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method wherein said indicator of CDI or CDAD is frequency of diarrhea. Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method wherein the frequency of said diarrhea is reduced to less than 4 unformed bowel movements (UBM) per day for 2 consecutive days. Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method, wherein said indicator of CDI or CDAD is stool consistency. Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method, wherein the stool consistency shows an improvement from Type 7 or Type 6 to Type 4 according to the Bristol Stool Form Scale. Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method wherein said indicator of CDI or CDAD is Clostridium difficile toxin B (TcdB). Another embodiment of the method of treating CDI or CDAD in a patient of the present invention is a method wherein said Clostridium difficile toxin B (TcdB) is absent.

[0052] The composition that can be used in the dosing regimen according to the present invention can be a pharmaceutical composition. Another embodiment of the present invention is a pharmaceutical composition comprising tiacumicin, its stereoisomer, its polymorph, or its pharmaceutically acceptable solvate for use in oral treatment of patients suffering from CDI or CDAD, thus comprising an initial treatment course in which 200 mg of the tiacumicin compound is orally administered twice daily, and the efficacy of the initial treatment course and one or more indicators of CDI or CDAD are evaluated by monitoring the change, and once one or more indicators have changed positively, 200 mg of the tiacumicin compound is administered to the patient every other day as an intermittent treatment course.

[0053] Compositions that can be used in the dosage regimen according to the invention may be aqueous suspensions, dry powders for aqueous suspension, dry granules for aqueous suspension, or dispersible tablets, capsules, or optionally film-coated tablets. Preferred compositions for oral administration are tablets, especially film-coated tablets. The term tablet also includes rapidly disintegrating tablets, among which are dispersible tablets and effervescent tablets.

[0054] The most commonly used tablet preparation methods include direct compression, dry granulation, and wet granulation. Direct compression involves compressing a mixture containing an active ingredient and excipients on a tablet press (L. Lachman et al., in: The Theory and Practice of Industrial Pharmacy, 3rd ed., 1986). In order to produce tablets with a uniform content of active ingredient, the mixture to be compressed must have both good flowability and compressibility. Good flowability cannot always be achieved by adding suitable excipients, such as lubricants, anti-adherents, and glidants, to the mixture. Therefore, the mixture is often granulated and then compressed.

[0055] Granulation is the process of forming spherical or regularly shaped agglomerates called granules from a powder mixture. It can be done by dry granulation and wet granulation. Granulation is also used to convert poorly cohesive powder mixtures into agglomerates that, when compressed, produce cohesive tablets. In the case of rapidly disintegrating tablets, it is advantageous for such ingredients to be coated, optionally in admixture with one or more excipients, in order to mask the taste of the active ingredient and / or to protect it from the possible adverse effects of light and / or moisture, and in the case of bendamustine, to protect the mucous membranes in the mouth from the adverse effects exerted by the active compound. For this purpose, the granules are preferably prepared and processed as further outlined below.

[0056] The term "particulate" refers to an agglomeration of particles, sometimes called a granule. Particulates are generally prepared by compaction and / or compression techniques (dry granulation) or by wet granulation techniques using a liquid, which may contain a dissolved binder for wet granulation (Remington's Pharmaceutical Sciences 18th ed. 1990, page 1641). Wet granulation techniques also include extrusion techniques. The term "particulate" therefore also includes pellets, spheroids, and extrudates, with pellets being preferred as examples of particulates. Pellets can be described as small particles of a certain density, approximately 1.0-1.6 mm in diameter, which are prepared by applying the pharmaceutical processes of extrusion and spheronization to a powder mixture. The active ingredient may advantageously be coated, optionally in admixture with one or more excipients, to mask the taste of the active ingredient and / or to protect the active ingredient from possible adverse effects of light and / or moisture and / or to protect the mucous membranes in the mouth from adverse effects exerted by the active compound.

[0057] The dosage forms that can be used in accordance with the treatment regimen of the present invention are preferably prepared by dry granulation techniques. Suitable techniques are described, for example, in Remington's Pharmaceutical Science, 18th ed. 1990, page 1644. These include dry granulation, roller compaction, and direct compression. When tablets are prepared by these techniques, it is even more advantageous to use direct compression. Preferably, dosage forms that can be used in accordance with the treatment regimen according to the present invention are provided with a coating. The coating has various purposes: it can serve to mask the taste of the active ingredient used in the composition, while at the same time protecting the active ingredient from possible adverse effects of light and / or moisture, such as oxidation, degradation, etc. Furthermore, the coating layer can protect the patient from damage to the oral mucosa by the active ingredient.

[0058] The coating layer can be applied to the dosage form by techniques well known in the art, such as spray coating and microencapsulation. In the case of tablets, the coating layer can be in the form of film coating, sugar coating, or compression coating. It is preferable to use the film coating process (Remington's Pharmaceutical Sciences 18th ed. 1990, page 1666). When the active ingredient requires the application of a coating to a rapidly disintegrating tablet, the individual granules can be appropriately coated and then compressed into a tablet.

[0059] It is preferred that it also contains a filler or diluent. Examples of such suitable compounds are: sugars that may be selected from the group consisting of sucrose, fructose, sorbitol, xylitol, maltitol, aspartame, erythritol, isomalt, trehalose, maltose, mannose, sorbose, xylose, dextran, dextrin, pullulan, mannitol, and lactose; - Microcrystalline cellulose or microfine cellulose; - starch, soluble starch or starch derivatives, such as hydroxyethyl starch; - Calcium carbonate, sodium chloride, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, sodium phosphate, carmellose potassium, carmellose calcium, carmellose sodium, synthetic aluminum silicate, etc. is.

[0060] Most preferred are microcrystalline cellulose and sugar selected from the group consisting of D-mannitol, erythritol, isomalt and trehalose.But considering the stability of the composition that contains fidaxomicin and xanthan gum under various storage conditions, it is preferable to use microcrystalline cellulose.In addition, the use of microcrystalline cellulose is advantageous for certain groups of patients who should not take sugar-containing compositions. The amount of microcrystalline cellulose should be as low as possible, but is not critical. The same applies if sugar is used.

[0061] Because rapid and uniform dispersion of fidaxomicin is important both in vitro and in vivo, the granules can further contain one or more disintegrants. Suitable disintegrants include cornstarch, potato starch, and partially pregelatinized starch, but so-called superdisintegrants can also be used, such as croscarmellose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and Amberlite IRP88. A preferred disintegrant is sodium starch glycolate, which is commercially available under the trademark Primojel®. This disintegrant has been shown to be effective in compositions containing either microcrystalline cellulose or sugar as a diluent. Furthermore, this has been shown to contribute to the ease of manufacturing the granule composition. A second disintegrant, such as partially pregelatinized starch, can be used. Compositions that can be used in accordance with the treatment regimens of the present invention can be aqueous suspensions, preferably in admixture with excipients such as buffers, preservatives, flavorings, sweeteners, and thickeners. Most preferably, the compositions contain flavorings and sweeteners to mask the taste of the Tiacumicin compounds.

[0062] Examples of buffering agents are hydrochloric acid, dilute hydrochloric acid, sulfuric acid, adipic acid and its salts, citric acid and its salts, gluconic acid and its salts, succinic acid and its salts, ascorbic acid and its salts, glacial acetic acid and its salts, acetic acid and its salts, tartaric acid and its salts, fumaric acid and its salts, maleic acid and its salts, lactic acid and its salts, malic acid and its salts, phosphoric acid and its salts, glycine, sodium bicarbonate, sodium carbonate, sodium hydroxide, magnesium hydroxide, and the like, as well as combinations of the above agents. Examples of preservatives include benzoic acid and its salts, edetic acid and its salts, salicylic acid and its salts, dibutylhydroxytoluene, sorbic acid and its salts, sodium dehydroacetate, parahydroxybenzoic acid and its salts, methylparaben, propylparaben, and the like, as well as combinations of the above preservatives.

[0063] Examples of flavoring agents are orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, oil of bitter orange, pine / pineapple oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, and the like, and combinations of the above flavoring agents. Examples of sweeteners include sucralose, aspartame, fructose, xylitol, glycyrrhizic acid and its salts, saccharin and its salts, stevia, sucrose, sorbitol, glucose, hydrogenated maltose starch syrup, maltitol, maltose, and the like, as well as combinations of the above sweeteners.

[0064] Examples of thickening agents are celluloses such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose; gums such as xanthan gum, guar gum, gellan gum, dextran, carrageenan; polyvinylpyrrolidone; specially treated microcrystalline celluloses such as water-dispersible celluloses (microcrystalline cellulose and sodium carboxymethyl cellulose); and combinations of the above thickening agents. Alternatively, granules that can be used according to the treatment regimen according to the invention in a mixture with extragranular excipients can be used to prepare dispersible tablets.

[0065] The tiacumicin compounds of the present invention may be used in combination with other active ingredients. For example, two or more tiacumicin compounds may be combined for oral treatment of CDI or CDAD. Polyclonal and monoclonal antibodies have shown effective effects in the treatment of CDI or CDAD. Polyclonal antibodies, for example, can facilitate patient treatment. Recent clinical trials have demonstrated that monoclonal antibodies combined with antibiotic therapy can reduce CDI recurrence in patients (Simon et al., Polyclonal antibody Therapies for Clostridium difficile Infection, Antibodies 2014, 3, 272-288). Therefore, a useful combination can be fidaxomicin combined with a monoclonal or polyclonal antibody. In particular, useful monoclonal antibodies for combination with fidaxomicin can reduce TcdA- and TcdB-mediated TNF-α and IL-1β expression. The following examples further illustrate the present invention, but those skilled in the art will appreciate that these examples are for illustrative purposes only and should not be construed as limiting the invention.

[0066] (Example 1) A Phase IIIb / IV randomized, controlled, open-label, parallel-group study (the Extension Fidaxomicin (FDX) study, also referred to as EXTEND with study number 2819-MA-1002) was conducted to compare the efficacy of vancomycin therapy with an intermittent dosing regimen of fidaxomicin therapy in sustained clinical cure of Clostridium difficile infection in an elderly population. The objectives of this study were to evaluate whether intermittent fidaxomicin regimen therapy was superior to standard vancomycin therapy in achieving sustained clinical cure of CDI 30 days after treatment completion, and to compare CDI recurrence at 40, 55, and 90 days.

[0067] [Table 2] TIFF0007774401000005.tif57165

[0068] Dosage basis Fidaxomicin (FDX) is thought to reduce recurrences primarily through less collateral damage to the colonic flora. The approved dosing regimen for FDX (200 mg q12h for 10 days) is not optimized for bacterial restoration and was selected based on existing practice with vancomycin and metronidazole. Therefore, the planned fidaxomicin (Dificlir™) study dose is not consistent with the current approved product description (SmPC) for Dificlir™ and was selected to maximize the product's attributes in treating CDI. Patients will receive 200 mg twice daily (bid) for 5 days on days 1 through 5. From days 6 through 25, patients will receive 200 mg once daily every other day (the first alternate-day dose will be given on day 7). This extended dosing allows a longer period for the protective flora to recover, prolonging the period during which C. difficile cells are suppressed and killing any dormant spores that germinate. Extended dosing also targets the early relapse period documented in the Phase 3 study—most relapses occurred during the first 15 days after treatment termination. By covering this period, this revised dosing regimen may reduce relapses to <10%, preferably <5%, and even more preferably <3%. The impact on the gut flora was limited, supporting the rationale for this study. The dose of vancomycin (Vancocin™) to be administered in this study will conform to the product description for Vancocin. Patients will receive 125 mg four times daily (qid) on days 1 through 10 for 10 days.

[0069] (Example 2) Phase IIIb / IV results described in Example 1 A Phase IIIb / IV randomized, controlled, open-label, parallel-group study (Extended Fidaxomicin (FDX) Study, also referred to as EXTEND with Study ID 2819-MA-1002) was conducted to compare the efficacy of standard vancomycin (VAN) therapy with that of an extended dosing regimen of fidaxomicin therapy in achieving sustained clinical cure of Clostridium difficile infection in an elderly population. The dosing regimen was as described in Table 1 of Example 1.

[0070] [Table 3]

[0071] The distribution of demographic and baseline characteristics was similar between the two treatment groups. In the combined group, the proportions of patients with 0, 1, and 2 previous CDI recurrences were 78.7%, 14.9%, and 6.4%, respectively. The mean number of unformed bowel movements in the last 24 hours before randomization was approximately 6.5 (±4.10 SD).

[0072] [Table 4] Sustained clinical cure was defined as a clinical response determined by the investigator at the cure test, with no recurrence of CDI between the cure test and the time of evaluation. [1] Difference between the two rates (extended fidaxomicin minus standard vancomycin) and the associated 95% confidence interval for the difference. [2] p-values ​​from the Cochran-Mantel-Haenszel test (general association) adjusted for randomization factors (CDI severity [severe or non-severe], presence or absence of cancer, age [≥75 or <75 years] and number of previous recurrences [0, 1, 2]). [3] Common odds ratio (OR) estimates and 95% confidence intervals.

[0073] [Table 5]

[0074] CDI recurrence was defined as the recurrence of diarrhea after test of cure to an extent greater than that recorded on day 10 for the vancomycin group or on day 25 for fidaxomicin for patients with a clinical response at test of cure, confirmed by a positive CDI test for toxin A / B, and requiring further CDI treatment. [1] The difference between the rates (extended fidaxomicin minus standard vancomycin) and the associated 95% confidence interval for the difference. [2] P values ​​from the Cochran-Mantel-Haenszel test (general association) adjusted for randomization factors (CDI severity [severe or nonsevere], presence or absence of cancer, age [≥75 or <75 years], and number of previous recurrences [0, 1, 2]). [3] Common odds ratio (OR) estimates and 95% confidence intervals. In the extended FDX group, 86.7% of patients achieved sustained clinical cure at 30 days after EOT compared with 62.9% in the standard VAN group (a difference of 23.8%). At day 55, the CDI recurrence rate was 3.5% in the extended FDX group compared with 16.1% (15 / 94) in the VAN group (a difference of -12.6%).

[0075] [Table 6] TIFF0007774401000010.tif98150

[0076] (Example 3) Detection of Clostridium difficile Toxins in Human Fecal Samples Detection of Clostridium difficile (C. diff) toxins A and B in human fecal samples was performed by ELISA. Samples analyzed were from clinical trial 2819-MA-1002 (EXTEND). The objective of EXTEND was to investigate whether extended fidaxomicin therapy was superior to standard vancomycin therapy in achieving sustained clinical cure of Clostridium difficile infection (CDI) 30 days after treatment completion (day 40 or 55) in patients aged ≥60 years. Samples were packed on dry ice and sent to LGC (Analytical lab in Fordham, Cambridgeshire, UK) and stored in a freezer (nominal -80°C) upon receipt. Stool samples were collected for each patient on day 0 (screening) and in the event of disease recurrence or scheduled outpatient visits. For patients participating in the Microbiome substudy, stool samples were collected on days 0 (screening), 5, 12, 27, 40, 55, and in the event of disease recurrence or scheduled outpatient visits. A total of 596 stool samples were collected during the study.

[0077] material C. difficile toxins A and B in human fecal samples were detected using the TECHLAB C. difficile Tox A / B II ELISA kit (product number T5015). All data collection, processing (statistics) and storage were performed using the following common data reduction software packages: PHERAstar FS reader control software and MARS data analysis software 2.10 (BMG Labtech, version 3.10), Watson™ v7.2 and Microsoft® Excel (version 2010). The assay readout was spectrophotometric dual-wavelength optical density (OD) expressed in absorbance units (AU), read at 450 nm and referenced at 620 nm. All samples were measured in duplicate. The presence (+) or absence (-) of toxin is reported along with the mean OD. The determination of each batch of test samples relies on data from QC samples that meet the acceptance criteria outlined in Table 5 below, with all positive QCs exceeding the cutoff value of >0.080 OD and negative QCs within the range of ≦0.080 OD. Every batch includes two separate sets of QC samples that are measured in duplicate. Precision was calculated between each set of OD replicates using the coefficient of variation (CV), which was required to be <20%.

[0078] [Table 7]

[0079] [Table 8]

[0080] (Example 4) Molecular Characterization of Clostridium difficile-Positive Human Fecal Samples LGC was appointed as the designated central laboratory for molecular characterization of Clostridium difficile-positive stool specimens in support of clinical trial 2819-MA-1002 (EXTEND), which aimed to evaluate whether extended fidaxomicin therapy was superior to standard vancomycin therapy in achieving sustained clinical cure of CDI 30 days after the end of treatment (day 40 or 55) in patients aged ≥60 years.

[0081] For each patient, stool samples were collected at screening (day 0) and in the event of disease recurrence or scheduled outpatient visits. For patients participating in the microbiota substudy, stool samples were collected on days 0 (screening), 5, 12, 27, 40, and 55, and in the event of disease recurrence or scheduled outpatient visits. Samples were analyzed for the presence of toxigenic C. difficile using a BioFire FilmArray Instrument, targeting both toxin A and toxin B genes, and for several other pathogens potentially causing diarrhea using the FilmArray Gastrointestinal (GI) Panels [RFIT-ASY-0104] and RFIT-ASY-0116 from bioMérieux (Basingstoke, UK). Samples were tested for the presence of 22 targets, which are common gastrointestinal pathogens and include viruses, bacteria, and parasites. Thawed samples were homogenized in molecular biology-grade water and analyzed individually on a BioFire FilmArray Instrument.

[0082] The following targets were tested: Campylobacter (C. jejuni / C. coli / C. upsaliensis), Clostridium difficile toxins A / B, Plesiomonas shigelloides, Salmonella, Vibrio (V. parahaemolyticus / V. vulnificus / V. cholera), Yersinia enterocolitica, and Streptococcus aureus. enterocolitica, Enteroaggregative E. coli (EAEC), Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC) lt / st, Shiga-like toxin-producing E. coli (STEC) stx1 / stx2, E. coli O157, Shigella / Enteroinvasive E. coli (EIEC), Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia lamblia (also known as G. intestinalis and G. duodenalis), adenovirus F40 / 41, astrovirus, norovirus GI / GII, rotavirus A, sapovirus (genogroups I, II, and IV), and human fecal samples from study 2819-MA-1002 were received from the central laboratory BARC (Industriepark Zwijnaarde 3B B-9052 Gent, Belgium). Samples were shipped to LGC on dry ice and stored in a freezer (nominal -80°C) upon receipt.

[0083] (Example 5) Comparison of various fidaxomicin treatment regimens with standard vancomycin therapy [Table 9]

[0084] (Example 6) A patient who tests positive for Clostridium difficile toxins A and B (using an appropriate assay known in the art) and has >5 UMB per day is treated with fidaxomicin 200 mg twice daily for the first treatment course. The number of UMBs is monitored daily to determine if the number of UMBs changes positively to ≤3 UMB per day. On day 2 of the first treatment course, the UMBs are reduced to 2 UMB per day and to 1 UMB per day on day 3. Since the number of UMBs is less than 4 per day and less than 3 per day for two consecutive days, the dosing regimen is switched to an intermittent treatment course in which the patient receives 200 mg fidaxomicin every other day starting on day 5 until Clostridium difficile toxins A and B test negative. Twelve days after initiating treatment, the presence of Clostridium difficile toxins A and B tests negative (using an appropriate assay known in the art).

[0085] (Example 7) A patient who tests positive for Clostridium difficile toxins A and B (using an appropriate assay known in the art) and has >5 UMB per day is treated with fidaxomicin 200 mg twice daily for the first treatment course. The number of UMB is monitored daily to determine if the number of UMB changes positively to ≤3 UMB per day. On days 9 and 10 of the first treatment course, the UMB is reduced to 3 UMB per day. Since the UMB is less than 4 UMB per day for two consecutive days, the dosing regimen is switched to an intermittent treatment course in which the patient receives 200 mg fidaxomicin every other day from day 12 until Clostridium difficile toxins A and B test negative. 27 days after initiating treatment, the presence of Clostridium difficile toxins A and B tests negative (using an appropriate assay known in the art).

[0086] (Example 8) Individual patient data for extended fidaxomicin treatment regimens [Table 10] [Industrial Applicability]

[0087] Treatment regimens with fidaxomicin compositions according to the present invention offer many advantages. Extending the treatment period from 10 to 20 or 25 days allows additional time for recovery of the patient's colonic flora, which may result in colonization resistance to subsequent CDI flare-ups / recurrences without the use of additional drug therapy.

[0088] Thus, a clear benefit of the dosing regimen of the present invention over the 20-day twice-daily regimen is that it allows for restoration of the gut flora, which is expected to lead to further reductions in relapses compared to existing doses (200 mg BID for 10 days), while providing equivalent efficacy in reducing C. difficile cells, spores, and toxins, but with one pack of fidaxomicin tablets (DIFICLIR™) rather than two of the standard 10-day packs.

[0089] If the proposed clinical trials based on the results of the in vitro tests are successful, then it is clear that, where possible, the recommended dosing regimen will be changed from 200 mg twice daily for 10 days to the dosing regimen according to the present invention. The expected benefit to patients, physicians, and society would be that reducing relapse to less than 5% would significantly change the cost-effectiveness argument in favor of fidaxomicin. Preferred embodiments of the present invention are as follows. [1] A tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof for use in the oral treatment of a patient with Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) by a dosing regimen, wherein the dosing regimen comprises: (1) administering to a patient 200 mg of a tiacumicin compound twice daily during an initial course of treatment; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching the patient to an intermittent treatment course in which 200 mg of a tiacumicin compound is administered to the patient every other day. Includes: [2] The Tiacumicin compound for use according to [1] above, wherein the Tiacumicin compound is fidaxomicin (R-Tiacumicin B). [3] The Tiacumicin compound for use according to [1] or [2], wherein the one or more indicators of CDI or CDAD are selected from the group consisting of (a) frequency of diarrhea, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH). [4] The Tiacumicin compound for use according to [3] above, wherein the indicator of CDI or CDAD is the frequency of diarrhea. [5] The Tiacumicin compound for use according to [4], wherein the frequency of diarrhea is reduced to less than four unformed bowel movements (UBM) per day for two consecutive days. [6] The Tiacumicin compound for use according to [5], wherein the frequency of diarrhea is reduced to less than three unformed bowel movements (UBM) per day for two consecutive days. [7] The Tiacumicin compound for use according to [3] above, wherein the indicator of CDI or CDAD is stool consistency. [8] The Tiacumicin compound for use according to [7] above, wherein the stool consistency is Type 7 or an improvement from Type 6 to Type 4 according to the Bristol Stool Form Scale. [9] The Tiacumicin compound for use according to [3] above, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin).

[10] The Tiacumicin compound for use according to [9] above, wherein the Clostridium difficile toxin B (TcdB toxin) and / or the Clostridium difficile toxin A (TcdA toxin) are absent.

[11] The tiacumicin compound for use according to [3] above, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B gene (tcdB).

[12] The tiacumicin compound for use according to

[11] above, wherein the Clostridium difficile toxin B gene (tcdB) is absent.

[13] The Tiacumicin compound for use according to [3] above, wherein the indicator of CDI or CDAD is Clostridium difficile surface antigen (GDH).

[14] The Tiacumicin compound for use according to

[13] above, wherein the Clostridium difficile surface antigen (GDH) is absent.

[15] The Tiacumicin compound for use according to any one of [1] to

[14] above, wherein the initial treatment course lasts for 5 days.

[16] The Tiacumicin compound for use according to any one of [1] to

[15] above, wherein the initial treatment course lasts for 3 to 10 days.

[17] The Tiacumicin compound for use according to any one of [1] to

[16] above, wherein the intermittent treatment course lasts for 20 days.

[18] The Tiacumicin compound for use according to any one of [1] to

[17] above, wherein the dosing regimen further comprises: 5) monitoring one or more indicators of intestinal flora; and 6) discontinuing the intermittent treatment course when one or more of the indicators of intestinal flora have changed favorably.

[19] The Tiacumicin compound for use according to

[18] above, wherein the indicator of intestinal bacterial flora is the number of Enterobacteriaceae bacteria.

[20] The Tiacumicin compound for use according to

[19] , wherein the total number of Enterobacteriaceae bacteria in the intestinal flora is reduced by 90% compared to the level before the first course of treatment.

[21] The Tiacumicin compound for use according to any one of [1] to

[20] above, wherein the recurrence of CDI or CDAD in patients is less than 10% 30 days after the end of treatment.

[22] The Tiacumicin compound for use according to any one of [1] to

[21] above, wherein the recurrence of CDI or CDAD in patients is less than 5% 30 days after the end of treatment.

Claims

1. 1. A pharmaceutical composition comprising a tiacumicin compound, a stereoisomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof for use in the oral treatment of a patient having Clostridium difficile infection (CDI) or Clostridium difficile-associated disease (CDAD) by a dosing regimen, wherein the dosing regimen comprises: (1) administering to a patient 200 mg of a tiacumicin compound twice daily for 3 to 9 days during an initial course of treatment; (2) monitoring the efficacy of the initial treatment course in the patient by monitoring changes in one or more indicators of CDI or CDAD; (3) assessing whether there is a positive change in one or more of the indicators; and (4) if there is a positive change in one or more of the indicators of CDI or CDAD, switching to an intermittent treatment course in which 200 mg of a tiacumicin compound is administered to the patient every other day. wherein said Tiacumicin compound is Fidaxomicin (R-Tiacumicin B).

2. 2. The pharmaceutical composition of claim 1, wherein the one or more indicators of CDI or CDAD are selected from the group consisting of: (a) diarrhea frequency, (b) stool consistency, (c) Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin), (d) Clostridium difficile toxin B gene (tcdB), and (e) Clostridium difficile surface antigen (GDH).

3. The pharmaceutical composition of claim 2, wherein the indicator of CDI or CDAD is the frequency of diarrhea.

4. 4. The pharmaceutical composition of claim 3, wherein the frequency of diarrhea is reduced to less than 4 unformed bowel movements (UBM) per day for 2 consecutive days.

5. 5. The pharmaceutical composition of claim 4, wherein the frequency of diarrhea is reduced to less than 3 unformed bowel movements (UBM) per day for 2 consecutive days.

6. The pharmaceutical composition according to claim 2, wherein the indicator of CDI or CDAD is stool consistency.

7. The pharmaceutical composition according to claim 6, wherein the stool consistency is an improvement from type 7 or type 6 to type 4 according to the Bristol Stool Form Scale.

8. The pharmaceutical composition according to claim 2, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B (TcdB toxin) and / or Clostridium difficile toxin A (TcdA toxin).

9. 9. The pharmaceutical composition of claim 8, wherein the Clostridium difficile toxin B (TcdB toxin) and / or the Clostridium difficile toxin A (TcdA toxin) are absent.

10. 3. The pharmaceutical composition of claim 2, wherein the indicator of CDI or CDAD is Clostridium difficile toxin B gene (tcdB).

11. 11. The pharmaceutical composition of claim 10, wherein the Clostridium difficile toxin B gene (tcdB) is absent.

12. The pharmaceutical composition of claim 2, wherein the indicator of CDI or CDAD is Clostridium difficile surface antigen (GDH).

13. 13. The pharmaceutical composition of claim 12, wherein the Clostridium difficile surface antigen (GDH) is absent.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the initial course of treatment lasts for 5 days.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the intermittent treatment course lasts for 20 days.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the dosing regimen further comprises the steps of: 5) monitoring one or more indicators of gut microbiota; and 6) discontinuing the intermittent treatment course if one or more of the indicators of gut microbiota change favorably.

17. The pharmaceutical composition according to claim 16, wherein the indicator of intestinal bacterial flora is the number of Enterobacteriaceae bacteria.

18. 18. The pharmaceutical composition of claim 17, wherein the total number of Enterobacteriaceae bacteria in the intestinal flora is reduced by 90% compared to the level before the first course of treatment.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the recurrence of CDI or CDAD in patients is less than 10% 30 days after the end of treatment.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the recurrence of CDI or CDAD in patients is less than 5% 30 days after the end of treatment.

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