Application of traditional Chinese medicine composition in preparation of medicine for treating recurrent clostridium difficile infection

Abstract

The invention belongs to the technical field of chemical drugs, and particularly relates to application of a traditional Chinese medicine composition in preparation of drugs for treating recurrent clostridium difficile infection.The traditional Chinese medicine composition is prepared from 10-50 g of fresh ginger, 3-20 g of honey-fried licorice roots, 5-30 g of ginseng, 3-20 g of dried ginger, 3-30 g of scutellaria baicalensis, 3-30 g of pinellia ternate, 3-15 g of coptis chinensis and 10-30 g of Chinese dates. The traditional Chinese medicine composition is excellent in clinical effect, and in sample research on high-risk crowds such as old people and immunosuppression CDI relapse patients, the treatment scheme of the vancomycin combined with the ginger heart-fire purging decoction is remarkably superior to vancomycin single-drug treatment in the aspect of continuous clinical response rate at the main curative effect end point. This benefit is achieved mainly by reducing the recurrence rate of CDI by more than 60%. The combined scheme shows a robust curative effect in key subgroups such as the elderly and immunosuppressive subgroups, is good in safety, does not increase extra adverse event risks, and particularly does not observe renal function impairment.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug technology, specifically relating to the application of traditional Chinese medicine compositions in the preparation of drugs for treating recurrent Clostridium difficile infection. Background Technology

[0002] Clostridium difficile infection ( Clostridioides difficile Hospital-acquired diarrhea (CDI) is one of the leading causes of diarrheal infections. The characteristics of *Clostridium difficile*, such as its easy resistance to drugs, long spore survival time in the external environment, and high transmissibility, lead to outbreaks of *Clostridium difficile*-induced diarrhea in hospitals and nursing facilities, threatening public health and attracting close attention from the medical community. The severity of CDI varies, ranging from mild diarrhea to serious complications such as pseudomembranous colitis, intestinal obstruction, sepsis including shock, megacolon, and death. Currently, antibiotics are the first-line treatment for CDI; however, the relapse rate is high, increasing the absolute risk of death in hospitalized patients and the incidence of fatal serious complications.

[0003] Furthermore, the applicant has observed in long-term clinical practice that existing drugs are ineffective in treating recurrent Clostridium difficile infection, particularly for high-risk groups such as elderly patients and those receiving immunotherapy. This is due to several factors: the high recurrence rate of Clostridium difficile infection, the highly virulent virulence of recurrent strains, exposure to acid-suppressing agents, and the fact that patients with recurrent CDI (rCDI) often fall into a vicious cycle of infection-recurrence due to decreased gut microbiota reconstruction, weakened immune defense, and impaired intestinal mucosal barrier. Recurrent CDI is categorized into symptomatic recurrence and positive CDI testing within 8 weeks of initial infection treatment. Treatment for subsequent recurrences depends on the number and duration of previous infections and the severity index of the CDI.

[0004] Although patent CN108478757A discloses the application of Shengjiang Xiexin Decoction in treating diarrhea caused by Clostridium difficile infection, demonstrating a certain therapeutic effect, the therapeutic effect is more stable than vancomycin, and recurrence is less likely. Shengjiang Xiexin Decoction comes from "Treatise on Febrile Diseases" written by Zhang Zhongjing of the Eastern Han Dynasty, but it does not disclose the therapeutic effect on recurrent Clostridium difficile infection. Summary of the Invention

[0005] The purpose of this invention is to provide the application of traditional Chinese medicine compositions in the preparation of drugs for treating recurrent Clostridium difficile infection, in order to solve the clinical problem of recurrence after treatment in high-risk groups of Clostridium difficile infection, especially to meet the clinical needs of elderly patients and people receiving immunosuppressive therapy, and to provide a new approach for the clinical treatment of recurrent Clostridium difficile infection, which has important clinical application prospects.

[0006] According to a first aspect of the present invention, the application of a traditional Chinese medicine composition in the preparation of a drug for treating recurrent Clostridium difficile infection is provided. The traditional Chinese medicine composition comprises the following ingredients: 10-50g of fresh ginger, 3-20g of prepared licorice root, 5-30g of ginseng, 3-20g of dried ginger, 3-30g of Scutellaria baicalensis, 3-30g of Pinellia ternata, 3-15g of Coptis chinensis, and 10-30g of jujube. The Pinellia ternata used in this invention is purified Pinellia ternata, which can be directly decocted with other medicinal materials. Using purified Pinellia ternata instead of washed Pinellia ternata simplifies the preparation process and improves safety.

[0007] The ingredients of these raw materials all comply with the 2025 edition of the Pharmacopoeia, and their sources are as follows: Ginger: ginger (Zingiber officinale), a plant in the ginger family. Zingiber officinale Rosc . Fresh rhizomes.

[0008] Prepared licorice root: A processed product of licorice root. Take licorice root slices and stir-fry them according to the honey-processing method (General Rule 0213) until they turn yellow to dark yellow and are no longer sticky. Remove them and let them cool. The licorice root is the legume plant *Glycyrrhiza uralensis*. Glycyrrhiza uralensis Fisch . licorice root Glycyrrhiza inflata Bat . Or licorice root Glycyrrhiza glabra L . The dried roots and rhizomes.

[0009] Ginseng: Panax ginseng, a plant belonging to the Araliaceae family. Panax ginseng The dried roots and rhizomes of CAMey.

[0010] Dried ginger: ginger (Zingiber officinale) is a plant in the ginger family. Zingiber officinale Rosc . The dried rhizome.

[0011] Scutellaria baicalensis: a plant of the Lamiaceae family. Scutellaria baicalensis The dried root of Georgi.

[0012] Pinellia: Pinellia ternata, a plant of the Araceae family Pinellia ternata (Thunb.) Breit . The dried tubers of Pinellia ternata. Prepared Pinellia ternata is a processed product of Pinellia ternata. The processing method is as follows: Take clean Pinellia ternata, separate them by size, soak or boil them in an 8% alum solution until there is no dry core inside and a slightly numbing sensation is felt on the tongue. Remove, wash, cut into thick slices, and dry. For every 100kg of clean Pinellia ternata, use 12.5kg of alum for the boiling method and 20kg of alum for the soaking method.

[0013] Coptis chinensis: a plant of the Ranunculaceae family, Coptis chinensis. Coptis chinensis Franch . Coptis chinensis triangularis Coptis deltoidea CYCheng et Hsiao or Yunlian Coptis teeta Dried rhizomes of Wall.

[0014] Jujube: a plant of the Rhamnaceae family, known as Ziziphus jujuba. Ziziphus jujuba Dried, ripe fruit of Mill.

[0015] In some embodiments, the traditional Chinese medicine composition consists of the following ingredients: 24g of fresh ginger, 18g of prepared licorice root, 18g of ginseng, 6g of dried ginger, 18g of scutellaria baicalensis, 18g of pinellia ternata, 6g of coptis chinensis, and 18g of jujube.

[0016] In some embodiments, the drug comprises a traditional Chinese medicine preparation derived from a traditional Chinese medicine composition, and vancomycin or a pharmaceutically acceptable salt thereof (i.e., the two used in combination). When the traditional Chinese medicine preparation is a dry powder of a traditional Chinese medicine composition extract (i.e., a powder), the weight ratio of the dry powder of the traditional Chinese medicine composition extract to vancomycin or a pharmaceutically acceptable salt thereof is 65:1 to 100:1, preferably, the weight ratio is 70:1 to 90:1, and more preferably, the weight ratio is 82:1.

[0017] In some embodiments, the drug further includes pharmaceutically acceptable excipients, which may be one or more of fillers, binders, disintegrants, lubricants, surfactants, or flavoring agents. The fillers are selected from one or more of starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, or glucose, and the binders are selected from one or more of cellulose derivatives, alginates, gelatin, or polyvinylpyrrolidone.

[0018] In some embodiments, the dosage forms of traditional Chinese medicine preparations include decoctions (or oral liquid preparations), mixtures, powders, capsules, granules, tablets, ointments, or pills.

[0019] In some embodiments, when the dosage form of the traditional Chinese medicine preparation is a compound, it is prepared by the following method: After weighing the raw materials, soak them in 8-10 times their weight of water for 30-60 minutes, then heat to boiling and maintain a gentle boil for 0.5-2 hours. After separation, obtain the filtrate and the residue. The residue is decocted 1-2 times, each time adding 6-8 times the weight of water from the raw materials, and each time decocting for 0.5-1 hours. After filtration, combine the filtrates to obtain the medicinal liquid. The medicinal liquid is then filtered and concentrated to a clear paste with a relative density of 1.05-1.10 (50-60℃). The compound is equivalent to a concentrated decoction. The main purpose of concentration is to reduce the volume of the medicinal liquid, making it easier for patients to take. While ensuring the concentration of effective ingredients and efficacy, it makes the daily dosage more acceptable, improves the taste, and increases compliance.

[0020] When the dosage form of traditional Chinese medicine preparation is powder, it is prepared by the following method: weigh the raw materials and soak them in 8-10 times their weight of water for 30-60 minutes, heat to boiling, maintain a gentle boil for 0.5-2 hours, and separate to obtain filtrate and dregs; decoct the dregs 1-2 times, adding 6-8 times their weight of water to the raw materials each time, and decoct for 0.5-1 hours each time, filter and combine the filtrates to obtain the medicinal liquid, filter and concentrate the medicinal liquid to a clear extract with a relative density of 1.05-1.10 (50-60℃), dry to obtain a dry extract, and pulverize the dry extract through an 80-100 mesh sieve to obtain dry extract powder. Drying can be achieved through vacuum drying at 60-65℃ and -0.06 to -0.08 MPa until the moisture content of the dried paste is ≤5%; or by drying in a hot air circulating oven at 60-70℃ until the moisture content is ≤5%; or by spray drying: inlet air 170-190℃, outlet air 80-90℃, peristaltic pump 20-40 mL / min, atomizing disc 1.5-2.0 mm, to obtain spray-dried paste powder.

[0021] According to another aspect of the present invention, the use of a combination drug in the preparation of a drug for treating recurrent Clostridium difficile infection is provided. The combination drug comprises a traditional Chinese medicine composition and vancomycin or a pharmaceutically acceptable salt thereof; wherein the traditional Chinese medicine composition comprises the following ingredients: 10-50g of fresh ginger, 3-20g of prepared licorice root, 5-30g of ginseng, 3-20g of dried ginger, 3-30g of Scutellaria baicalensis, 3-30g of Pinellia ternata, 3-15g of Coptis chinensis, and 10-30g of jujube. For example, the traditional Chinese medicine composition comprises the following ingredients: 24g of fresh ginger, 18g of prepared licorice root, 18g of ginseng, 6g of dried ginger, 18g of Scutellaria baicalensis, 18g of Pinellia ternata, 6g of Coptis chinensis, and 18g of jujube.

[0022] In some embodiments, the dosage form of the traditional Chinese medicine composition includes decoction, compound preparation, powder, capsule, granule, tablet, ointment or pill.

[0023] In some embodiments, when the traditional Chinese medicine preparation is in powder form, each 1g of the combined drug contains 0.980g to 0.991g of the traditional Chinese medicine composition.

[0024] In some embodiments, when the traditional Chinese medicine preparation is in powder form, the weight ratio of the traditional Chinese medicine preparation to the vancomycin or a pharmaceutically acceptable salt thereof is 65:1 to 100:1; preferably, the weight ratio of the traditional Chinese medicine preparation to vancomycin or a pharmaceutically acceptable salt thereof is 70:1 to 90:1; more preferably, the weight ratio of the traditional Chinese medicine preparation to vancomycin or a pharmaceutically acceptable salt thereof is 82:1.

[0025] The traditional Chinese medicine composition of this invention exhibits excellent clinical efficacy. In a study of high-risk (elderly and immunosuppressed) patients with recurrent CDI, the treatment regimen of vancomycin combined with Shengjiang Xiexin Decoction significantly outperformed vancomycin monotherapy in terms of the primary efficacy endpoint of sustained clinical response rate (81.3% vs. 56.3%, absolute difference 25.0%). This benefit is primarily achieved by reducing the CDI recurrence rate by more than 60%. This combination regimen demonstrated robust efficacy in key subgroups such as the elderly and immunosuppressed individuals, with a good safety profile, without increasing the risk of additional adverse events, and in particular, no renal impairment was observed.

[0026] Furthermore, the traditional Chinese medicine composition of this invention significantly reduced the Clostridium difficile load in the feces of two types of model mice, improved diarrhea symptoms, promoted weight recovery, and effectively repaired colonic tissue structure. Histological observation revealed that the model group mice had severe epithelial shedding of the colonic mucosa, disordered crypt structure, and significant inflammatory cell infiltration. After intervention with the composition of this invention, epithelial continuity and crypt morphology were significantly restored, and inflammatory cells were significantly reduced, suggesting that it has a significant repair effect on colonic damage caused by rCDI. At the molecular level, the traditional Chinese medicine composition of this invention significantly upregulated the expression of tight junction proteins ZO-1 and Occludin, enhancing the intestinal epithelial barrier function, while significantly downregulating the expression of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β, inhibiting the inflammatory response. Compared with the positive control drug vancomycin alone, the composition of this invention has greater advantages in reducing diarrhea, promoting weight recovery, and promoting barrier repair.

[0027] The traditional Chinese medicine composition of the present invention is for patients with recurrent Clostridium difficile infection (rCDI), whose disease characteristics and intestinal flora status are significantly different from those of patients with initial CDI. Furthermore, the dosage of the traditional Chinese medicine composition has been adjusted to enhance the therapeutic effect on the recurrent group. Attached Figure Description

[0028] Figure 1 The data represents the Clostridium difficile load in mice at different time points. A is a line graph of Clostridium difficile load during the modeling and treatment phases, and B is a graph of Clostridium difficile load on the last day of treatment for each group.

[0029] Figure 2 This is one of the fecal scores for mice in different groups at different times.

[0030] Figure 3 This represents one of the rates of change in body weight of mice in different groups over different number of days.

[0031] Figure 4 This is one of the histopathological staining methods for colon tissue from the CON group mice. The scale bar is 100 μm and 200 × 100 μm.

[0032] Figure 5Pathological staining of colon tissue from the Aged-MOD group mice. Scale bar: 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells; red arrows indicate inflammatory cell infiltration.

[0033] Figure 6 This is one of the pathological staining methods for colon tissue in VAN mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells; red arrows indicate inflammatory cell infiltration.

[0034] Figure 7 This is one of the histopathological staining methods for colon tissue in SXD-H group mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells; red arrows indicate inflammatory cell infiltration.

[0035] Figure 8 The colon tissue of SXD-L group mice was stained for pathological purposes. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells; red arrows indicate inflammatory cell infiltration.

[0036] Figure 9 The colon tissue of the Comb-H group mice was stained for pathological treatment. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0037] Figure 10 The colon tissue of the Comb-L group mice was stained for pathological treatment. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0038] Figure 11 It is one of the expression levels of IL-1β mRNA in colon tissue.

[0039] Figure 12 It is one of the expression levels of IL-6 mRNA in colon tissue.

[0040] Figure 13 This represents the expression level of TNF-α mRNA in colon tissue.

[0041] Figure 14 This is one of the expression levels of ZO-1 mRNA in colon tissue.

[0042] Figure 15 This represents one of the expression levels of Occludin mRNA in colon tissue.

[0043] Figure 16 The two figures represent the Clostridium difficile load in mice of different number of days. A is a line graph of Clostridium difficile load during the modeling and treatment phases, and B is a graph of Clostridium difficile load on the last day of treatment for each group.

[0044] Figure 17 The second part is the fecal score of mice in different groups at different times.

[0045] Figure 18 The figures represent the weight change rates of mice in each group over different number of days. A is a line graph showing the weight change rate of mice during the treatment phase, and B is a graph showing the weight change rate of mice in each group on the last day of treatment.

[0046] Figure 19 The second example of histopathological staining of colon tissue from the CON group mice, scale bar 100μm, 200×.

[0047] Figure 20 This is the second example of histopathological staining of colon tissue from DXM-MOD mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0048] Figure 21 This is the second example of histopathological staining of colon tissue from VAN mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0049] Figure 22 This is the second example of histopathological staining of colon tissue from SXD-H mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0050] Figure 23 This is the second example of histopathological staining of colon tissue from SXD-L group mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells; red arrows indicate inflammatory cell infiltration.

[0051] Figure 24 This is the second example of histopathological staining of colon tissue from the Comb-H group mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0052] Figure 25 This is the second example of histopathological staining of colon tissue from the Comb-L group mice. The scale bar is 100μm, 200×. Black arrows indicate exfoliated mucosal epithelial cells, and red arrows indicate inflammatory cell infiltration.

[0053] Figure 26 This represents the second level of IL-1β mRNA expression in colon tissue.

[0054] Figure 27 This represents the second level of IL-6 mRNA expression in colon tissue.

[0055] Figure 28 This represents the second level of TNF-α mRNA expression in colon tissue.

[0056] Figure 29 This represents the second level of ZO-1 mRNA expression in colon tissue.

[0057] Figure 30 This represents the second level of Occludin mRNA expression in colon tissue.

[0058] In the picture: *P<0.05, **P<0.01, ***P<0.001. Detailed Implementation

[0059] The present invention will be further described in detail below with reference to specific embodiments. It is worth noting that the following embodiments are only for better explaining the content of the present invention and do not limit the scope of protection of the present invention. Process steps not disclosed in the embodiments are prior art. Unless otherwise specified, all raw materials are commercially available. Among them, "slight boiling" refers to the state in which the liquid has just reached the boiling point and a few bubbles are emerging. At this time, the liquid temperature is between 93-100°C (standard atmospheric pressure).

[0060] The traditional Chinese medicine composition used in the experimental example consisted of: 24g fresh ginger, 18g prepared licorice root, 18g ginseng, 6g dried ginger, 18g scutellaria baicalensis, 18g prepared pinellia ternata, 6g coptis chinensis, and 18g jujube; jujube: split. A dry powder formulation of the traditional Chinese medicine was prepared as follows: The raw materials were soaked in water equal to 10 times their weight for 30 minutes, heated to boiling, and kept at a gentle boil for 1 hour. The filtrate and residue were separated. The residue was decocted twice, each time with water equal to 6 times the weight of the raw materials, and decocted for 0.5 hours each time. After filtration, the filtrates were combined to obtain a medicinal liquid. The medicinal liquid was concentrated by filtration to a clear extract with a relative density of 1.05–1.10 (60℃), spray-dried to obtain a dry extract, and then pulverized through an 80-mesh sieve to obtain a dry extract powder.

[0061] In the experimental examples of this invention, a traditional Chinese medicine preparation made from a traditional Chinese medicine composition was used in combination with vancomycin. The weight ratio of the traditional Chinese medicine preparation to vancomycin in the combined drug was approximately 82:1 ± 10%. Each 1g of the combined drug contained approximately 12mg of vancomycin and approximately 988mg of dried powder from the traditional Chinese medicine preparation. When converted to body weight, the total intake of the combined drug of approximately 4.2g / kg can achieve a given exposure level of approximately 50mg / kg of vancomycin.

[0062] To demonstrate the efficacy of the traditional Chinese medicine composition of this invention in treating recurrent Clostridium difficile infection, the following experiment was conducted.

[0063] Experimental Example 1: Clinical Efficacy of the Traditional Chinese Medicine Composition of the Present Invention This prospective, randomized controlled study aims to evaluate whether combining Shengjiang Xiexin Decoction with standard vancomycin treatment can effectively improve the sustained clinical response rate in high-risk CDI relapse patients and to investigate its potential biological mechanisms.

[0064] I. Research Methods 1. Study Design and Patients This study was a multicenter, prospective, randomized controlled clinical trial that enrolled 32 eligible patients with relapsed chronic obstructive inflammatory disease (CDI). These patients were all elderly (≥65 years old) or immunosuppressed, including patients with HIV / AIDS, patients on long-term immunosuppressive therapy, and post-organ transplant patients. All patients signed informed consent forms. Patients were randomly assigned 1:1 to two treatment groups: Control group (n=16): Received standard vancomycin monotherapy.

[0065] Combined treatment group (n=16): In addition to standard vancomycin treatment, patients received oral administration of Shengjiang Xiexin Decoction, one of the compositions of the present invention.

[0066] The study process complied with the requirements of the CONSORT statement. All randomized patients completed the study protocol and were included in the final intention-to-treat (ITT) analysis.

[0067] 2. Therapeutic endpoint Primary efficacy endpoint: Sustained Clinical Response. Defined as clinical cure (relief of diarrhea symptoms) achieved after completing a standard 10-day course of vancomycin treatment, with no recurrence of CDI during the subsequent follow-up period up to week 8 (day 56).

[0068] Secondary efficacy endpoints included initial clinical cure rate (day 10), rCDI relapse rate (by week 8), median time to resolution of diarrhea symptoms, and rCDI-related hospitalization rate.

[0069] 3. Safety assessment Throughout the study, all treatment-related adverse events (TEAEs) that occurred during treatment were systematically recorded and evaluated, including their severity and relevance to the study drug, and key safety indicators such as renal function were closely monitored.

[0070] II. Data Results 1. Patient baseline characteristics There were no statistically significant differences between the two groups in terms of age, sex, history of CDI, disease severity, comorbidities, and key laboratory indicators (all p>0.05), indicating that the randomization was balanced. More than 75% of the patients in this study cohort were elderly individuals aged ≥65 years or in an immunosuppressed state, successfully including the pre-defined high-risk target population.

[0071] Table 1. Baseline demographics and clinical characteristics of patients

[0072] 2. Therapeutic effect analysis Primary endpoint: The sustained clinical response rate in the combination therapy group was significantly higher than that in the control group (81.3% vs. 56.3%), with an absolute risk difference of 25.0% (95% CI: 1.2% to 48.8%; p=0.04).

[0073] Secondary endpoint: The initial clinical cure rate was 93.8% in both groups, with no significant difference. However, in terms of relapse prevention, the relapse rate in the combination therapy group was significantly lower than that in the control group (13.3% vs. 40.0%). The median time to resolution of diarrhea was slightly shorter in the combination therapy group, and the rCDI-related hospitalization rate was also lower.

[0074] Table 2 Primary and key secondary efficacy endpoints

[0075] 3. Subgroup analysis In the pre-specified key high-risk subgroups of elderly (≥65 years) and immunosuppressed patients, the combination therapy showed a consistent and robust trend toward efficacy benefit. Particularly in immunosuppressed patients, the absolute difference in sustained clinical response rate reached 30.6%, suggesting that this therapy may provide the greatest benefit to the group with the weakest gut microbiota restoration capacity.

[0076] Table 3. Stratified analysis of primary endpoints by key subgroups

[0077] Experiment 2: Efficacy Validation Study of Different Doses of Shengjiang Xiexin Decoction Alone and in Combination with Vancomycin in Aged and Immunosuppressed rCDI Mouse Models I. Research Methods 1. Clostridium difficile culture Clostridium difficile strains were inoculated onto Columbia blood agar plates and cultured at 37°C for 7 days under standard anaerobic conditions. Clostridium difficile was collected from the culture medium using a sterile loop and then resuspended in phosphate-buffered saline (PBS). To isolate Clostridium difficile spores, the suspension was heat-treated at 65°C for 20 min to eliminate vegetative cells. The heat-treated suspension was centrifuged at 1500 rpm, a centrifuge radius of 18.9 cm, and 25°C for 5 min, washed 2–3 times with PBS, and the supernatant was discarded. The resulting precipitate was resuspended in liquid culture medium and stored at -80°C for later use.

[0078] 2. Construction, grouping, and administration of rCDI mouse model (1) Aged rCDI mouse model Forty-two 20-month-old male C57BL / 6 mice were selected and numbered after one week of acclimatization. The mice were randomly divided into seven groups (n=6 per group) using SPSS random number table: blank control group (CON), aged recurrent Clostridium difficile infection model group (Aged-MOD), vancomycin group (VAN), high-dose ginger-based decoction group (SXD-H), low-dose ginger-based decoction group (SXD-L), vancomycin + low-dose ginger-based decoction group (Comb-L), and vancomycin + high-dose ginger-based decoction group (Comb-H).

[0079] The control group mice had normal food and water intake and were not subjected to modeling. The model group and other treatment groups were given 0.5 mg / mL cefoperazone instead of drinking water for 5 consecutive days to disrupt the intestinal flora, followed by 2 days of normal water intake. On day 8, except for the CON group, each mouse was administered approximately 1 × 10⁻⁶ cefoperazone via gavage. 6 CFU-containing Clostridium difficile spores were kept on a normal diet and water supply from day 8 to day 12 to encourage germination and colonization of the spores in the intestine. From day 12 onwards, vancomycin 1 mg / animal / day was administered by gavage for 5 consecutive days (until day 17) to eliminate most of the vegetative cells of Clostridium difficile, leaving only the spores, thereby inducing infection recurrence against the backdrop of dysbiosis.

[0080] After modeling (days 18-24), each group underwent intervention according to the grouping protocol. Administered medication by gavage at 9:00 AM daily for 7 consecutive days. The CON and Aged-MOD groups received an equal volume of physiological saline by gavage; the VAN group received vancomycin 50 mg / kg daily by gavage; the SXD-H and SXD-L groups received Shengjiang Xiexin Decoction 16.4 g / kg and 8.2 g / kg daily by gavage, respectively; the Comb-H group received vancomycin 50 mg / kg + Shengjiang Xiexin Decoction 16.4 g / kg daily by gavage; and the Comb-L group received vancomycin 50 mg / kg + Shengjiang Xiexin Decoction 8.2 g / kg daily by gavage. Mice were sacrificed after treatment, and tissue and fecal samples were collected for subsequent testing.

[0081] (2) Immunosuppressed rCDI mouse model Forty-two 6-week-old male C57BL / 6 mice were selected and numbered after one week of acclimatization. Using SPSS random number table, the mice were randomly divided into seven groups of six mice each: blank control group (CON), immunosuppressed recurrent Clostridium difficile infection model group (DXM-MOD), vancomycin group (VAN), and high-dose Shengjiang Xiexin Decoction group (SXD-H), low-dose Shengjiang Xiexin Decoction group (SXD-L), vancomycin + high-dose Shengjiang Xiexin Decoction group (Comb-H), and vancomycin + low-dose Shengjiang Xiexin Decoction group (Comb-L).

[0082] The blank control group mice had normal food and water intake and were not subjected to modeling. The model group and other treatment groups were given 0.5 mg / mL cefoperazone + 0.1 mg / mL dexamethasone in place of drinking water for 5 consecutive days to disrupt the intestinal flora, followed by 2 days of normal water intake. On day 8, except for the CON group, each mouse was inoculated by gavage with approximately 1 × 10⁻⁶ cefoperazone / dexamethasone. 6 CFU-containing Clostridium difficile spores were fed a normal diet and water intake from day 8 to 12 to encourage spore germination and colonization in the intestine. From day 12 onwards, dexamethasone at 0.1 mg / mL was administered to replace drinking water for 5 consecutive days (until day 17), along with gavage administration of vancomycin 1 mg / animal / day to eliminate most of the vegetative cells of Clostridium difficile, leaving only spores, thereby inducing infection recurrence against the backdrop of dysbiosis.

[0083] After modeling (days 18–24), each group underwent intervention according to the grouping protocol. Administered medication by gavage at 9:00 AM daily for 7 consecutive days. The CON and DXM-MOD groups received an equal volume of physiological saline by gavage; the VAN group received vancomycin 50 mg / kg daily by gavage; the SXD-H group received 16.4 g / kg of Shengjiang Xiexin Decoction daily by gavage; the SXD-L group received 8.2 g / kg of Shengjiang Xiexin Decoction daily by gavage; the Comb-H group received vancomycin 50 mg / kg + 16.4 g / kg of Shengjiang Xiexin Decoction daily by gavage; and the Comb-L group received vancomycin 50 mg / kg + 8.2 g / kg of Shengjiang Xiexin Decoction daily by gavage. Mice were sacrificed after treatment, and tissue and fecal samples were collected for subsequent testing.

[0084] 3. Stool score The fecal score is assessed and classified using a three-level standard: (1) Formed, the feces retain their shape and are brown, with a score of 1 point; (2) Semi-formed or soft, does not pour out, and is yellow, with a score of 2 points; (3) Liquid, easily poured out, and is yellow, with a score of 3 points.

[0085] 4. RT-qPCR detection of Clostridium difficile load in mouse feces Total microbial DNA was extracted from mouse feces using a fecal DNA extraction kit, and the resulting DNA solution was stored at -20°C. The level of Clostridium difficile toxin B in mouse feces was detected using an absolute quantification method. Primer and probe sequences are shown in Table 4.

[0086] Table 4 Primer and probe sequences

[0087] Reaction conditions: The standard two-step PCR amplification procedure was used: Step 1, pre-denaturation at 95℃ for 30s, 1 cycle; Step 2, denaturation at 95℃ for 3s, 50℃ for 30s, 40 cycles.

[0088] 5. RT-qPCR detection of tight junction proteins and inflammatory factors in colonic tissue The expression of ZO-1, Occludin, TNF-α, IL-6, and IL-1β in colon tissue was detected, with GAPDH used as an internal control gene. Total RNA was extracted using the Trizol method. RNA was converted to cDNA using a reverse transcription kit from Beijing LABLEAD Biotechnology Co., Ltd. RT-qPCR was used for detection, employing a two-step amplification program: Step 1: 95°C pre-denaturation for 5 minutes; Step 2: 95°C denaturation for 10 seconds, followed by annealing / extension at 60°C for 30 seconds, repeated for 40 cycles. The reaction volume was 20 μL, containing 10 μL of SYBR Green Master Mix, 1 μL each of forward and reverse primers, 2 μL of DNA template, and 6 μL of nuclease-free water. The primer sequences used are shown in Table 5.

[0089] Table 5 Primer sequences

[0090] 6. Colon tissue pathological staining Fresh mouse colon tissue was collected, laid flat and rolled into a Swiss-roll, fixed in 4% paraformaldehyde, then embedded in paraffin, with a section thickness of about 4 μm, and stained with hematoxylin and eosin (H&E). The pathological changes of the colon sections were observed under a microscope.

[0091] II. Research Results 1. Pharmacodynamic evaluation of SXD in aged rCDI mice On day 8, all mice except the CON group received gavage stimulation with Clostridium difficile spores. By day 12, the fecal Clostridium difficile load in all groups was significantly increased, indicating that the infection model was successfully established. After treatment with vancomycin from day 12 to day 17, the fecal Clostridium difficile load in mice showed a decreasing trend on day 14, but rebounded on day 17, indicating infection recurrence.

[0092] During the drug intervention phase, the bacterial load of *Clostridium difficile* in the Aged-MOD group continued to increase from day 17. The bacterial load in the SXD-H and SXD-L groups, treated with *Ginger-based Decoction for Clearing Heart Fire* alone, remained high on day 19, while the bacterial load in the VAN, Comb-H, and Comb-L groups showed a significant decreasing trend. From day 19 to day 24, except for the DXM-MOD and CON groups, the *Clostridium difficile* load in all other groups decreased significantly. On day 24 of the intervention phase (the last testing day), compared with the Aged-MOD group, the *Clostridium difficile* load in the SXD-H, SXD-L, Comb-H, and Comb-L groups was significantly lower (P<0.001). Among these, the groups receiving vancomycin treatment (VAN group and the combination therapy group) showed a significantly greater decrease in bacterial load than the group treated with *Ginger-based Decoction for Clearing Heart Fire* alone, suggesting that *Ginger-based Decoction for Clearing Heart Fire* is less effective than vancomycin in inhibiting *Clostridium difficile* proliferation. Furthermore, there was no significant difference in the degree of bacterial load reduction between the Comb-H group and the Comb-L group.

[0093] Figure 2 The results showed that, except for the CON group, the fecal scores of all other groups of mice exhibited a decreasing trend, indicating that the diarrhea symptoms were gradually alleviated. Among them, the SXD-H group and the Comb-H group showed the most significant recovery. By day 24 of the intervention phase (the last test day), the fecal scores of the SXD-H group, the Comb-L group, and the Comb-H group were significantly lower than those of the Aged-MOD group, indicating that high-dose ginger decoction and its combination with vancomycin treatment can effectively improve the severity of diarrhea in mice.

[0094] The results of the changes in body weight of mice in different groups at different times are as follows: Figure 3 As shown, the results indicated that, except for the CON group, the body weight of mice in all groups decreased to varying degrees from day 17 to day 19. From day 19 to day 21, the body weight of all groups except the Aged-MOD group gradually recovered. By day 24 of the intervention phase, compared with the Aged-MOD group, the body weight of the SXD-H group and the Comb-H group was significantly increased (P<0.05), suggesting that increasing the dosage of Shengjiang Xiexin Decoction can significantly promote the recovery of body weight in mice.

[0095] H&E staining results ( Figure 4–10) This visually demonstrates the pathological changes in the colonic tissue of each group of mice. In the CON group, the colonic mucosa structure was intact, with tightly packed and continuous epithelial cells, regular crypt morphology, and no obvious inflammatory cell infiltration in the lamina propria, maintaining normal tissue structure. The Aged-MOD group, however, showed significant tissue damage: mucosal epithelial cell shedding and defects, diffuse inflammatory cell infiltration in the lamina propria, and inflammation spreading to deeper layers, reflecting severe damage to the colonic tissue after age-related rCDI modeling. After drug intervention, the pathological damage in the SXD-H group was significantly improved compared to the Aged-MOD group; epithelial defects in the areas indicated by blue arrows were reduced, inflammatory cell infiltration decreased, and crypt structure gradually recovered. The Comb-H group showed the most significant colonic tissue repair, with good mucosal epithelial continuity, a significant reduction in inflammatory cells, regular crypt arrangement, and an overall tissue structure close to normal, demonstrating that high-dose ginger-based decoction combined with vancomycin can significantly repair and protect the colonic tissue of immunosuppressed rCDI mice. Compared to the Comb-L group, the Comb-H group showed more outstanding performance in restoring mucosal epithelial integrity.

[0096] To systematically evaluate the regulatory effects of various treatment regimens on intestinal barrier function and inflammatory response in aged rCDI mice, this study examined the mRNA expression levels of tight junction proteins (ZO-1, Occludin) and typical pro-inflammatory factors (TNF-α, IL-6, IL-1β). Figures 11 to 15 The results showed that the expression of ZO-1 and Occludin was significantly downregulated in the Aged-MOD group, indicating damage to the intestinal epithelial barrier structure and increased permeability. At the same time, the expression of TNF-α, IL-6 and IL-1β was significantly increased, reflecting obvious inflammatory response and immune imbalance in the colon tissue of the model mice.

[0097] Following drug intervention, all treatment groups showed varying degrees of improvement in the aforementioned abnormalities. Occludin expression was significantly upregulated in all treatment groups, while ZO-1 expression showed the most significant recovery in the SXD-H and Comb-H groups, with the remaining groups also showing an upward trend. This suggests that high-dose Shengjiang Xiexin Decoction can effectively repair the damaged intestinal epithelial barrier and improve the integrity of the mucosal structure. Notably, the expression of ZO-1 and Occludin in the Comb-H group was significantly higher than that in the Comb-L group (P<0.05), further indicating that increasing the dose of Shengjiang Xiexin Decoction can enhance its protective and reconstructive effects on the intestinal mucosal barrier.

[0098] Regarding inflammatory factors, the expression levels of TNF-α, IL-6, and IL-1β in all treatment groups were significantly lower than those in the Aged-MOD group (P<0.01 or P<0.001), indicating that drug intervention effectively alleviated the intestinal inflammatory response. Among them, the vancomycin intervention group showed the most significant effect in inhibiting the expression of inflammatory factors, while the high-dose ginger decoction had a more prominent effect in promoting the recovery of tight junction proteins.

[0099] 2. Pharmacodynamic evaluation of SXD in immunosuppressed rCDI mice On day 8, all mice except the CON group received gavage stimulation with Clostridium difficile spores. By day 12, the fecal Clostridium difficile load in all groups was significantly increased, indicating successful establishment of the infection model. Following vancomycin treatment from days 12 to 17, the fecal Clostridium difficile load in mice showed a decreasing trend on day 14, but rebounded on day 17, indicating infection recurrence. Figure 16 The second group of mice with Clostridium difficile load at different number of days.

[0100] During the drug intervention phase, the bacterial load of *Clostridium difficile* in the DXM-MOD group continued to increase from day 17. The bacterial load in the SXD-H and SXD-L groups, treated with *Ginger-based Decoction for Clearing Heart Fire* alone, remained high on day 19, while the bacterial load in the VAN, Comb-H, and Comb-L groups showed a significant decreasing trend. From day 19 to day 24, the *Clostridium difficile* load in all groups except the DXM-MOD and CON groups decreased significantly. On day 24 of the intervention phase (the last testing day), the *Clostridium difficile* load in the SXD-H, SXD-L, Comb-H, and Comb-L groups was significantly lower than that in the DXM-MOD group (P<0.001). Among these, the groups receiving vancomycin treatment (VAN group and the combination therapy group) showed a significantly greater decrease in bacterial load than the group treated with *Ginger-based Decoction for Clearing Heart Fire* alone, suggesting that *Ginger-based Decoction for Clearing Heart Fire* is less effective than vancomycin in inhibiting *Clostridium difficile* proliferation. Furthermore, there was no significant difference in the degree of bacterial load reduction between the Comb-H group and the Comb-L group, indicating that... Figure 16 .

[0101] Except for the CON group, the fecal scores of mice in all other groups showed a decreasing trend, indicating that the diarrhea symptoms gradually subsided. The SXD-H and Comb-H groups showed the most significant recovery. By day 24 of the intervention phase (the last test day), the fecal scores of the SXD-H and Comb-H groups were significantly lower than those of the DXM-MOD group (P<0.01 and P<0.05, respectively), indicating that high-dose ginger-based decoction combined with vancomycin treatment can effectively improve the severity of diarrhea in mice. Figure 17 .

[0102] Except for the CON group, the body weight of mice in all groups decreased to varying degrees from day 17 to day 19. From day 19 to day 21, except for the DXM-MOD group, the body weight of the other groups gradually recovered. By day 24 of the intervention phase, compared with the DXM-MOD group, the body weight of the SXD-H group and the Comb-H group was significantly increased (P<0.001 and P<0.01, respectively). Notably, the weight recovery in the Comb-H group was significantly greater than that in the Comb-L group (P<0.01), suggesting that increasing the dosage of Shengjiang Xiexin Decoction can significantly promote the weight recovery of mice. Figure 18 .

[0103] H&E staining results ( Figures 19 to 25 The results visually demonstrated the pathological changes in the colonic tissue of mice in each group. The CON group showed intact colonic mucosal structure, tightly and continuously arranged epithelial cells, regular crypt morphology, and no obvious inflammatory cell infiltration in the lamina propria, maintaining normal tissue structure. In the DXM-MOD group, significant tissue damage was observed: mucosal epithelial cell shedding and defects, diffuse infiltration of numerous inflammatory cells in the lamina propria, and extension into the submucosa, indicating successful establishment of the immunosuppressive rCDI model and severe colonic damage.

[0104] After drug intervention, the pathological damage in the SXD-H group was significantly improved compared to the DXM-MOD group. Epithelial defects in the areas indicated by blue arrows were reduced, inflammatory cell infiltration decreased, and crypt structures gradually recovered. The colonic tissue repair was most significant in the Comb-H group, with good mucosal epithelial continuity, a significant reduction in inflammatory cells, regular crypt arrangement, and an overall tissue structure close to normal. This demonstrates that high-dose ginger-based decoction combined with vancomycin can significantly repair and protect the colonic tissue of immunosuppressed rCDI mice. Compared to the Comb-L group, the Comb-H group showed more outstanding performance in restoring mucosal epithelial integrity.

[0105] To systematically evaluate the regulatory effects of various treatment regimens on intestinal barrier function and inflammatory response in immunosuppressive rCDI mice, this study examined the mRNA expression levels of tight junction proteins (ZO-1, Occludin) and typical pro-inflammatory factors (TNF-α, IL-6, IL-1β). The results are as follows: Figures 26 to 30 As shown in the figure. The results showed that the expression of ZO-1 and Occludin was significantly downregulated in the DXM-MOD group, indicating that the intestinal epithelial barrier structure was damaged and permeability was increased; at the same time, the expression of TNF-α, IL-6 and IL-1β was significantly increased, reflecting that there was a significant inflammatory response and immune imbalance in the colon tissue of the model mice.

[0106] Following drug intervention, all treatment groups showed varying degrees of improvement in the aforementioned abnormalities. ZO-1 expression was significantly upregulated in all treatment groups, while Occludin expression showed the most significant recovery in the SXD-H and Comb-H groups, with the remaining groups also showing an upward trend. This suggests that high-dose Shengjiang Xiexin Decoction can effectively repair the damaged intestinal epithelial barrier and improve the integrity of the mucosal structure. Notably, ZO-1 expression in the Comb-H group was significantly higher than that in the Comb-L group (P<0.01), and Occludin expression was also significantly higher in the Comb-L group (P<0.05), further indicating that increasing the dose of Shengjiang Xiexin Decoction can enhance its protective and reconstructive effects on the intestinal mucosal barrier.

[0107] Regarding inflammatory factors, the expression levels of TNF-α, IL-6, and IL-1β in all treatment groups were significantly lower than those in the DXM-MOD group (P<0.05, P<0.01, or P<0.001), indicating that drug intervention effectively alleviated the intestinal inflammatory response. Among them, the vancomycin intervention group showed the most significant effect in inhibiting the expression of inflammatory factors, while the high-dose ginger-based decoction had a more prominent effect in promoting the recovery of tight junction proteins.

[0108] Clostridium difficile infection (CDI) has a high relapse rate and is difficult to treat, especially in the elderly and immunocompromised individuals. The aforementioned study, through analysis of clinical data from rCDI patients, found that the composition of this invention—high-dose ginger-based decoction combined with vancomycin—demonstrated good adjuvant therapeutic effects in elderly patients and those receiving immunosuppressive therapy, effectively reducing relapse rates and improving clinical symptoms. Based on this clinical finding, this study further established elderly rCDI mouse models and immunosuppressed rCDI mouse models at the animal level to verify the efficacy of SXD.

[0109] Experimental results showed that the high-dose traditional Chinese medicine composition of this invention, combined with vancomycin, significantly reduced the Clostridium difficile load in the feces of two types of model mice, improved diarrhea symptoms, promoted weight recovery, and effectively repaired colonic tissue structure. Histological observation revealed that the colonic mucosal epithelial shedding, crypt structure disorder, and significant inflammatory cell infiltration were observed in the model group mice. However, after intervention with the high-dose traditional Chinese medicine composition of this invention combined with vancomycin, epithelial continuity and crypt morphology were significantly restored, and inflammatory cells were significantly reduced, suggesting that it has a significant repair effect on colonic damage caused by rCDI. At the molecular level, Shengjiang Xiexin Decoction significantly upregulated the expression of tight junction proteins ZO-1 and Occludin, enhancing the intestinal epithelial barrier function, while significantly downregulating the expression of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β, inhibiting the inflammatory response. Compared with the positive control drug vancomycin alone, the composition of this invention has greater advantages in reducing diarrhea, promoting weight recovery, and promoting barrier repair.

[0110] Based on clinical data, it was found that the combination of Shengjiang Xiexin Decoction and vancomycin has a good therapeutic effect on elderly patients and those with rCDI under immunosuppression. To further verify its pharmacodynamic effects, an elderly mouse model of rCDI and an immunosuppressed mouse model was established, and the efficacy of the high-dose traditional Chinese medicine composition of the present invention combined with vancomycin was systematically evaluated at the whole, tissue, and molecular levels. The results showed that the high-dose traditional Chinese medicine composition of the present invention combined with vancomycin could significantly reduce Clostridium difficile load, improve diarrhea symptoms, promote weight recovery, and significantly repair colonic tissue structure. In summary, combining clinical and animal experimental results, the high-dose traditional Chinese medicine composition of the present invention combined with vancomycin shows good prevention and treatment potential in high-risk groups such as the elderly and those with weakened immune function.

[0111] In addition, the formula dosage in the existing patent CN108478757A is the standard dosage of the classic formula "Shengjiang Xiexin Decoction" (12g of fresh ginger, 9g of prepared licorice root, 9g of ginseng, 3g of dried ginger, 9g of scutellaria baicalensis, 9g of pinellia ternata, 3g of coptis chinensis, and 9g of jujube). The animal equivalent dosage is approximately 8.2g / kg. Targeting the pathological characteristics of patients with recurrent Clostridium difficile infection (rCDI), the above experiment established and compared two combined administration groups: Comb-L group: vancomycin 50 mg / kg + Shengjiang Xiexin Decoction 8.2 g / kg; Comb-H group: vancomycin 50 mg / kg + Shengjiang Xiexin Decoction 16.4 g / kg.

[0112] Experimental results showed that the Comb-H group was superior to the Comb-L group in reducing pathological damage and improving the intestinal barrier, suggesting that the combined medication with increased dosage had a more significant effect in preventing recurrence. Therefore, the above experimental results prove that the herbal composition of this invention (16.4g / kg SXD + 50mg / kg VAN) is superior in efficacy to the scheme of patent CN108478757A (8.2g / kg SXD + 50mg / kg VAN), demonstrating the technological advancement of dosage optimization.

[0113] The above descriptions are merely some specific embodiments of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the inventive concept of the present invention, and all such modifications and improvements fall within the scope of protection of the present invention.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a drug for treating recurrent Clostridium difficile infection, characterized in that, The traditional Chinese medicine composition consists of the following ingredients: 10-50g fresh ginger, 3-20g prepared licorice root, 5-30g ginseng, 3-20g dried ginger, 3-30g scutellaria baicalensis, 3-30g pinellia ternata, 3-15g coptis chinensis, and 10-30g jujube.

2. The application according to claim 1, characterized in that, The traditional Chinese medicine composition consists of the following ingredients: 24g fresh ginger, 18g prepared licorice root, 18g ginseng, 6g dried ginger, 18g scutellaria baicalensis, 18g pinellia ternata, 6g coptis chinensis, and 18g jujube.

3. The application according to claim 1 or 2, characterized in that, The dosage forms of the traditional Chinese medicine preparations include decoctions, mixtures, powders, capsules, granules, tablets, ointments, or pills.

4. The application according to claim 3, characterized in that, When the dosage form of the traditional Chinese medicine preparation is powder, it is prepared by the following method: After weighing the raw materials, soak them in 8-10 times their weight of water for 30-60 minutes, then heat to boiling and maintain a gentle boil for 0.5-2 hours. After separation, obtain the filtrate and the dregs. Boil the dregs 1-2 times, adding 6-8 times their weight of water to the raw materials each time. After filtration, combine the filtrates to obtain the medicinal liquid. Filter and concentrate the medicinal liquid to a clear paste with a relative density of 1.05-1.

10. Dry the paste to obtain the dry paste. Pulverize the dry paste through an 80-100 mesh sieve to obtain the dry paste powder.

5. The use of a combination drug in the preparation of a drug for treating recurrent Clostridium difficile infection, wherein the combination drug is composed of a traditional Chinese medicine composition and vancomycin or a pharmaceutically acceptable salt thereof, wherein the traditional Chinese medicine composition comprises the following components: Fresh ginger 10-50g, prepared licorice root 3-20g, ginseng 5-30g, dried ginger 3-20g, scutellaria baicalensis 3-30g, pinellia ternata 3-30g, coptis chinensis 3-15g, jujube 10-30g.

6. The application according to claim 5, characterized in that, The dosage forms of the traditional Chinese medicine preparations include compound preparations, powders, capsules, granules, tablets, ointments, or pills.

7. The application according to claim 6, characterized in that, When the traditional Chinese medicine preparation is in powder form, the weight ratio of the traditional Chinese medicine preparation to the vancomycin or its pharmaceutically acceptable salt is 65:1 to 100:

1.

8. The application according to claim 7, characterized in that, The weight ratio of the traditional Chinese medicine preparation to the vancomycin or its pharmaceutically acceptable salt is 70:1 to 90:

1.

9. The application according to claim 8, characterized in that, The weight ratio of the traditional Chinese medicine preparation to the vancomycin or its pharmaceutically acceptable salt is 82:

1.

10. The application according to any one of claims 6-9, characterized in that, When the dosage form of the traditional Chinese medicine preparation is powder, it is prepared by the following method: After weighing the raw materials, soak them in 8-10 times their weight of water for 30-60 minutes, then heat to boiling and maintain a gentle boil for 0.5-2 hours. After separation, obtain the filtrate and the dregs. Boil the dregs 1-2 times, adding 6-8 times their weight of water to the raw materials each time. After filtration, combine the filtrates to obtain the medicinal liquid. Filter and concentrate the medicinal liquid to a clear paste with a relative density of 1.05-1.

10. Dry the paste to obtain the dry paste. Pulverize the dry paste through an 80-100 mesh sieve to obtain the dry paste powder.

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