Chinese expert consensus on intestinal microecology and management of digestive tract complications related to tumor treatment (version 2022)

Abstract

The human gut microbiota represents a complex ecosystem that is composed of bacteria, fungi, viruses, and archaea. It affects many physiological functions including metabolism, inflammation, and the immune response. The gut microbiota also plays a role in preventing infection. Chemotherapy disrupts an organism's microbiome, increasing the risk of microbial invasive infection; therefore, restoring the gut microbiota composition is one potential strategy to reduce this risk. The gut microbiome can develop colonization resistance, in which pathogenic bacteria and other competing microorganisms are destroyed through attacks on bacterial cell walls by bacteriocins, antimicrobial peptides, and other proteins produced by symbiotic bacteria. There is also a direct way. For example, Escherichia coli colonized in the human body competes with pathogenic Escherichia coli 0157 for proline, which shows that symbiotic bacteria compete with pathogens for resources and niches, thus improving the host's ability to resist pathogenic bacteria. Increased attention has been given to the impact of microecological changes in the digestive tract on tumor treatment. After 2019, the global pandemic of novel coronavirus disease 2019 (COVID-19), the development of novel tumor-targeting drugs, immune checkpoint inhibitors, and the increased prevalence of antimicrobial resistance have posed serious challenges and threats to public health. Currently, it is becoming increasingly important to manage the adverse effects and complications after chemotherapy. Gastrointestinal reactions are a common clinical presentation in patients with solid and hematologic tumors after chemotherapy, which increases the treatment risks of patients and affects treatment efficacy and prognosis. Gastrointestinal symptoms after chemotherapy range from nausea, vomiting, and anorexia to severe oral and intestinal mucositis, abdominal pain, diarrhea, and constipation, which are often closely associated with the dose and toxicity of chemotherapeutic drugs. It is particularly important to profile the gastrointestinal microecological flora and monitor the impact of antibiotics in older patients, low immune function, neutropenia, and bone marrow suppression, especially in complex clinical situations involving special pathogenic microbial infections (such as clostridioides difficile, multidrug-resistant Escherichia coli, carbapenem-resistant bacteria, and norovirus).

INTRODUCTION

We organized domestic experts in the fields of oncology, hematology, clinical pharmacy, gastroenterology, immunology of infection, nutrition, microecology testing, and basic microecology to communicate and discuss gastrointestinal complications in the clinical treatment of malignant tumors. Guidelines are available on nausea, vomiting, anorexia, diarrhea and constipation from the Chinese Society of Clinical Oncology, the Infectious Diseases Society of America, National Comprehensive Cancer Network, the American Society of Clinical Oncology, the Multinational Association of Supportive Care in Cancer, and MASCC/European Society for Medical Oncology (MASCC/ESMO). Based on the quality of the evidence, recommendations and a consensus were made with different strengths for the main treatment strategies for oral and gastrointestinal symptoms and digestive system complications following chemotherapy. It considers the treatment of most non-infectious and infectious complications and the corresponding care measures and combines special precautions for coronavirus disease 2019 (COVID-19) epidemic prevention, intestinal microecology detection, Chinese traditional medicine, and fecal microbiota transplantation (intestinal microbiota transplantation) to provide a practical evidence-based consensus for clinicians and contribute to a set of guidelines.[¹²³]

The level of consensus evidence and the strength of the recommendations were rated with reference to the guidelines for the diagnosis and treatment of the abovementioned societies [Tables 1 and 2]. This consensus was formulated to further understand the key issues regarding the impact of intestinal microecology on tumor therapy, learn and absorb new research progress, consider the evidence that has been developed in recent years, especially after the COVID-19 epidemic, and incorporate the recommendations of other guidelines. Finally, we organized relevant experts in the fields of tumor and microecology to discuss and put forward the Chinese expert consensus on intestinal microecology and management of digestive tract complications related to tumor treatment (version 2022), which may be used as a reference for clinicians in their practical work and provides a basis for in-depth research in the fields of tumor and microecology.

Table 1: Expert recommendation level description

Table 2: Level of evidence-based medical evidence of recommended protocols

PART I: EXPERT RECOMMENDATIONS ON THE MANAGEMENT OF SIDE EFFECTS OF CHEMOTHERAPY FOR TUMORS WITH SYMPTOMS

One: Nausea, vomiting, and anorexia caused by chemotherapy

Chemotherapy-induced nausea and vomiting (CINV) are the main adverse effects following treatment. It is important to predict the specific emetogenic chemotherapeutic drugs for treatment. Before initiating a chemotherapeutic drug regimen (optional), a multi-disciplinary cooperative team including clinicians, care team, clinical pharmacy specialists, nutritionists, and psychologists are required to carefully read the instructions for the drugs, refer to the literature, formulate complete prescriptions and prevention protocols, and regularly review and update them.[⁴⁵]

Expert recommendation

1. To treat nausea and vomiting caused by chemotherapy, the drugs with the highest therapeutic index are serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, neurokinin 1 receptor (NK1R) antagonists, and glucocorticoid (dexamethasone). Related drugs may be used in combination. (Level I recommendation)
2. Highly emetogenic risk chemotherapy regimens: Antiemetic regimens based on cisplatin, anthracyclines plus cyclophosphamide (AC regimen), and other highly emetogenic agents are recommended in combination with 5-HT3 receptor antagonists, dexamethasone, and NK1R antagonists. (Level I recommendation) Patients receiving an AC regimen + glucocorticoid regimen (such as the RCHOP regimen for non-Hodgkin's lymphoma) can add palonosetron on the 1^st day. (Level I recommendation)
3. Moderately emetogenic-risk chemotherapy regimens: When administering carboplatin-based chemotherapy, it is recommended to use an NK1R antagonist, 5-HT3 receptor antagonist, and dexamethasone in combination on the 1^st day. If combined with delayed vomiting, it is recommended to continue the use of the 5-HT3 receptor antagonist. (Level I recommendation)
4. Low and extremely low emetogenic-risk chemotherapy regimens: Patients treated with low emetogenic-risk medications may be treated with an NK1R antagonist, 5-HT3 receptor antagonist, or dexamethasone monotherapy, or combination therapy. If vomiting has occurred in the past, patients may be administered preventive antiemetics. (Level I recommendation)
5. Electrolyte levels such as potassium, sodium, and magnesium as well as electrocardiogram (ECG) QT intervals should be evaluated before chemotherapy and ECG monitoring is recommended during chemotherapy. Benzodiazepines may prevent anticipatory vomiting and CINV can be prevented from the initial chemotherapy cycle. (Level II recommendation)
6. Assessment of anorexia and dietary intake: Symptoms such as depression, dysgeusia, pain, nausea, and constipation during chemotherapy may cause patients to become anorexic. All patients should be evaluated for nutritional status and weight loss by a professional dietitian prior to chemotherapy, especially patients with cachexia at the beginning of treatment, who may require psychotherapy. (Level I recommendation)
7. Clinically focused assessment: Conduct a detailed medical history, nutritional history, and any self-treatment with traditional Chinese medicine. A physical examination evaluates subcutaneous fat thickness measurement, muscle atrophy, and hypotonia, sacral or ankle edema, or ascites. The objective indicators of nutrition during chemotherapy are continuous weight measurement and dietary intake assessment, with regular detection of albumin and transferrin. (Level II recommendation)
8. Dietary counseling: Estimate the protein and calorie requirements of patients during chemotherapy. The diet during chemotherapy should be limited to digestible and cooked foods, while avoiding potentially harmful meals (e.g., carbonated beverages, fried foods, and high-protein nondigestible diets) and avoiding sour, salty, or dry foods. If the patient is unable to swallow food or liquid, it is necessary to supplement with parenteral liquid and/or nutritional support. Supplements of unproven efficacy are not recommended and both the patient and the caregiver should know about and implement them. (Level II recommendation)
9. Application of Chinese herbal medicine: If the patient is willing to take Chinese herbal medicine during the interval of chemotherapy, a doctor of traditional Chinese medicine can be consulted to jointly evaluate the patient's condition, select a Chinese herbal medicine based on syndrome differentiation, and consider the interaction between Chinese herbal medicine and other drugs. (Level III recommendation).

ORAL AND GASTROINTESTINAL MUCOSITIS

Approximately 40% of patients receiving conventional chemotherapy will develop oral mucositis. For hematopoietic stem cell transplants, the incidence of mucositis in patients who received pretreatment can reach 80–95%. A variety of factors, including chemotherapy drugs, dose, route of administration, frequency, and patient tolerance, may be associated with mucositis. If there is secondary or colonized microbial infective mucositis, the time may be prolonged. The pathological mechanism of mucositis involves a series of stages: a) initiation-radiotherapy and chemotherapy can directly damage DNA, which results in the production of inflammatory cytokines; b) upregulation-initiation phase damage activates the NF-κB pathway (nuclear factor-kappa B); c) the feedback loop amplifies signal conduction. These three stages occur before the appearance of clinically significant mucositis, followed by ulcer, inflammation, and healing, which takes about 10–14 days.[⁶⁷]

Expert recommendation

1. Gastrointestinal and oral mucositis in chemotherapy patients often peak on the seventh day after treatment. In severe cases, there may be marked erosion with severe pain and an inability to consume food and water. If it is estimated that severe mucositis is present, it is necessary for clinicians and pharmaceutical experts to conduct a pre-chemotherapy evaluation. The Multidisciplinary Team (MDT), including clinicians, nursing team, clinical pharmacists, and nutritionists, is required before the use of chemotherapeutic drugs (regimens). It is necessary to read the instructions for the chemotherapy drugs in detail, refer to the literature, formulate complete prescriptions and prevention regimens, and regularly review and update them. (Level I recommendation)
2. Factors assessing the extent and severity of mucositis should include: Specific chemotherapy drugs, dosage, mode, and frequency of administration, presence of oral diseases before treatment, concurrent use of radiotherapy, and individual tolerance differences of the patient. The cytotoxic drugs that most frequently cause severe oral mucositis include bleomycin, cytarabine, doxorubicin, etoposide, fluorouracil, and methotrexate. (Level I recommendation)
3. Preventive oral treatment before and between chemotherapy is recommended, including a comprehensive oral examination before treatment, such as tooth scaling, treatment of caries, and tooth extraction. Note: Patients with multiple myeloma should avoid tooth extraction during zoledronic acid treatment. Only patients with chronic periodontal disease can be evaluated for dental intervention before chemotherapy. (Level I recommendation)
4. Specific prevention strategies: For patients receiving pretreatment chemotherapeutic regimens containing fluorouracil or high-dose melphalan, oral cold therapy (ice saline gargle for 20–30 min four times a day) is recommended. (Level II recommendation)
5. It is estimated that patients who develop oral ulcer should receive oral care once every 4 hours. Gargle with saline and a 2.5% sodium bicarbonate dilute solution, gargle and wipe the mouth after each meal, and clean teeth effectively with a soft toothbrush. (Level II recommendation)
6. Low-intensity ultraviolet light treatment is helpful to prevent oral mucositis in patients with hematological malignancies receiving high-dose chemoradiotherapy. In foreign countries, when high-dose chemotherapy is administered with pre-treatment protocols with high-risk of severe mucositis, Palifermin (recombinant human keratinocyte growth factor) may be administered intravenously to prevent oral mucositis and hematological diseases centers with drugs may try it. (Level II recommendation)
7. Oral herpes simplex virus has a high reactivation rate. When receiving induction chemotherapy or pretreatment chemotherapy, the use of acyclovir antiviral therapy is recommended. (Level I recommendation)
8. Patients with severe oral mucositis complicated with pain can use lidocaine mucilage locally, and if necessary, general anesthetics (e.g., fentanyl transdermal patch) or oral mucosal protective agents (e.g., Ipsos oral gel). (Level I recommendation)
9. Patients with oropharyngeal candidiasis may be given a local antifungal therapy (nystatin dissolved in saline gargle) or miconazole oral patch. If they have fever and other symptoms, such as a positive G or GM test, systemic antifungal therapy is needed. (Level I recommendation)
10. Based on the influence of oral microecology on the process of tumor chemotherapy, qualified medical units should carry out the detection of oral microecology changes before and after chemotherapy. (Level III recommendation)

PERSISTENT DIARRHEA CAUSED BY CHEMOTHERAPY

Chemotherapy-related diarrhea (CRD) is a common symptom of cancer patients after treatment and seriously affects patients' quality of life. Patients with severe CRD often require hospitalization and their lives are at risk because of dehydration and possible infection. Diarrhea is most commonly associated with the use of chemotherapy drugs (e.g., fluorouracil and capecitabine), certain molecular targeted drugs (e.g., sorafenib, sunitinib), and immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, and pembrolizumab).[⁸⁹¹⁰¹¹]

Expert recommendation

1. Severe CRD can affect daily life, delay chemotherapy, require hospitalization for supportive care, or even be life-threatening in more severe cases. Patients should be assessed for stool frequency, stool characteristics, and accompanying signs or symptoms, such as colic, nausea, or vomiting above grade 2, decreased physical status, fever, dizziness, hypotension, neutropenia, bleeding manifestations, dehydration, chest pain, and previous admission for CRD. Patients with grade 3/4 diarrhea and patients with grade 1/2 diarrhea with complications require intravenous infusion, ECG monitoring, and electrolyte detection and evaluation. (Level I recommendation)
2. Laboratory tests (standard biochemical screening, whole blood cell count and electrolyte series including magnesium) should be geared toward the complications and causes of CRD. If the patient has severe (grade 3 or 4) diarrhea, persistent mild to moderate (grade 1 or 2) diarrhea, or diarrhea with neutropenia, fever or bloody stool, blood and stool culture, and examination of toxigenic strains of Clostridium difficile are required. Patients with bloody diarrhea should have a stool culture for the detection of enterohemorrhagic Escherichia coli and Shiga toxin. (Level I recommendation)
3. For patients with fever, peritoneal irritation, or bloody diarrhea, CT scans of the abdomen and pelvis should be done and a surgeon should be consulted. Endoscopy is not required in the vast majority of patients, but should be considered in refractory patients and in patients with chronic diarrhea (i.e., persistent diarrhea throughout the chemotherapy cycle) or bloody diarrhea. Other causes of diarrhea during chemotherapy should be identified, including fat or bile acid malabsorption, lactose intolerance, small intestinal bacterial overgrowth, or infectious causes. (Level II recommendation)
4. The initial non-pharmaceutical measures for prevention include avoiding foods that may aggravate diarrhea. Adopting a semi-liquid diet and oral rehydration, avoiding foods containing lactose, and stopping the use of drugs that cause diarrhea, such as stool softeners and laxatives. Loperamide is recommended as the initial treatment for CRD. For mild to moderate uncomplicated CRD, an initial dose of 4 mg is recommended, followed by 2 mg every 4 hours. For patients with severe (grade 3 or 4) diarrhea, including patients with mild to moderate diarrhea complicated by moderate to severe abdominal colic, grade 2 or more severe nausea/vomiting, decreased physical status, fever, sepsis, neutropenia, definitive bleeding or dehydration, or patients with mild to moderate diarrhea without complications after 24 hours of loperamide treatment, high-dose loperamide is recommended (4 mg initially, 2 mg every 2 hours thereafter). Octreotide is recommended for CRD patients who have failed treatment with loperamide. The initial treatment dose is 100 or 150 μg, three times a day by subcutaneous injection. (Level II recommendation)
5. There is no consensus for the role of oral antibiotics in patients with CRD. Intravenous antibiotics should be given to patients with fever, neutropenia, hypotension, peritoneal irritation signs, or bloody diarrhea. If diarrhea does not stop after treatment with loperamide and high-dose octreotide, upper gastrointestinal endoscopy, or capsule gastroscopy is recommended. Japanese scholars use small bowel capsule endoscopy to observe the whole small intestinal mucosa, including any bleeding, malignant tumor, and mucosal damage. A pathological biopsy is performed to evaluate whether cytomegalovirus (CMV) or Clostridium difficile infection (CDI) is present. (Level III recommendation)
6. Patients with severe CRD can resume the same chemotherapeutic regimen after 48 hours without diarrhea and 48 hours without antidiarrheal drugs. All patients with grade 2 or more severe diarrhea in the previous treatment cycle should have their chemotherapy dose reduced. Regarding the influence of intestinal diarrhea and intestinal microecology on chemotherapy, it is recommended to detect any intestinal microecological changes before and after chemotherapy and hematopoietic stem cell transplantation. (Level II recommendation)

Part II: The disposition of chemotherapy combined with special complications and the recommendation of intestinal microecology management experts

EVALUATION AND MANAGEMENT OF NEUTROPENIC FEVER

Chemotherapy treatment causes bone marrow suppression and damage to the gastrointestinal mucosa, which will lead to an increase in invasive infections due to colonized bacteria and/or fungal translocation across the intestinal mucosal surface. In patients with neutropenia, the neutrophil-mediated inflammatory response may not be obvious, and fever may be the earliest or even the only sign of infection. It is necessary to recognize neutropenic fever as early as possible and start empirical systemic antimicrobial therapy in time to avoid sepsis syndrome and death. Neutropenia is defined as an absolute neutrophil count (ANC) <1500/μL, while severe neutropenia is defined as ANC <500/μL or ANC is expected to drop below 500/μL in the next 48 hours, and extremely severe neutropenia is defined as ANC <100/μL. ANC <500/μ L will increase the risk of clinically significant infection, and patients with prolonged neutropenia (>7 days) will have a higher risk. ANC <100/μ L will increase the risk of bacteremia infection.[¹²¹³¹⁴]

Expert recommendation

1. High-intensity cytotoxic chemotherapy can cause severe and sometimes persistent neutropenia, which may require hospitalization for fever or possibly fatal infection. For patients with a high-risk of infection, prophylactic use of antibacterial, antiviral, and antifungal drugs can reduce complications. The MDT, including clinicians, pharmacy specialists, and infection microbiology experts, is required to make a pre-judgment of whether a chemotherapy regimen is likely to cause agranulocytosis before it is used. (Level I recommendation)
2. The evaluation of neutropenic fever is particularly important for reducing the risk of serious complications, because it will determine treatment options, including the duration and severity of agranulocytosis, intravenous administration of antibiotics, and prolonged hospitalization. Patients with high-risk neutropenia (ANC < 500/μ L) and persistent agranulocytosis (>7 days) or evidence of comorbidity should be evaluated. Severe neutropenia most often occurs in patients undergoing hematopoietic stem cell transplantation, primary induction chemotherapy, and consolidated high-dose chemotherapy for acute leukemia. (Level I recommendation)
3. Initial empirical treatment of agranulocytosis fever in patients with high-risk neutropenia is a medical emergency. Empirical broad-spectrum antimicrobial therapy should be started immediately, and bactericidal antibiotics are recommended. At the same time, blood culture and secretion samples of suspicious parts should be taken. The selection of initial antibiotics is based on patient history, past medical history, allergy history, symptoms and signs, recent antibiotic use, drug sensitivity results of culture, and nosocomial infection. For patients suspected of central venous catheter (CVC), skin, or soft tissue infection or hemodynamic instability, the antimicrobial spectrum should be expanded to cover all possible pathogens (e.g., drug-resistant Gram-negative bacteria, Gram-positive bacteria, anaerobic bacteria, and fungi). (Level I recommendation)
4. Empirical treatment of persistent fever: Only persistent fever alone does not require adjustment of the initial antibiotic regimen. The initial regimen should be adjusted for patients with a risk for drug-resistant microbial infection, clinical and hemodynamic instability, and positive blood cultures suggestive of drug-resistant bacterial infection. Empirical addition of antifungal drugs is recommended when fever persists after 4–7 days of treatment with broad-spectrum antibacterial drugs and the source of infection is unknown. (Level I recommendation)
5. Removal of CVC and PICC catheters is recommended for patients with catheter-associated bloodstream infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, Pseudomonas aeruginosa, or fast-growing nontuberculous mycobacteria. (Level I recommendation)
6. Neutropenic diet: Because gastrointestinal mucosal injury is prone to serious intestinal bacterial infection, there is a lack of systematic clinical data to evaluate a neutropenic diet. Patients with severe neutropenia are still recommended to eat fully cooked and digestible food until their neutrophils recover. (Level II recommendation)
7. It is recommended that patients with high-risk neutropenia, previous intestinal infection, and disseminated infection of Gram-negative bacteria undergo intestinal microecological detection and monitoring before and after chemotherapy. (Level II recommendation)

NEUTROPENIC ENTEROCOLITIS

Neutropenic enterocolitis is a fatal necrotizing enterocolitis, which mainly occurs in patients with neutropenia. The pathogenesis of this disease may include mucosal damage caused by cytotoxic drugs, severe neutropenia, and an impaired defense against microbial invasion. Microbial infection can result in multilayer necrosis of the intestinal wall. The cecum is usually involved and the lesions often extend into the ascending colon and terminal ileum. Patients with severe neutropenia also experience fever and abdominal pain, which is usually located in the lower right abdomen. Neutropenic enterocolitis should be considered. Symptoms usually appear in the 3^rd week after receiving cytotoxic chemotherapy, when neutropenia is the most severe and the patient has a fever. Neutropenic enterocolitis is usually diagnosed according to characteristic CT findings.[¹⁵¹⁶¹⁷]

Expert recommendation

1. All patients suspected of neutropenic colitis should undergo an abdominal CT examination. CT findings include intestinal wall thickening, mesenteric cable sign, dilatation of the intestinal cavity, mucosal strengthening, and intestinal wall pneumatosis. (Level II recommendation)
2. A variety of bacteria and/or fungi including Gram-negative bacilli, Gram-positive cocci, anaerobic bacteria (e.g., Clostridium septicum), and Candida spp., frequently infiltrate the intestinal wall, which results in the occurrence of multiple microbial infections. Bacteremia or fungemia is also common and is usually caused by intestinal microorganisms, such as Pseudomonas spp. or yeasts (e.g., Candida). (Level II recommendation)
3. Neutropenic enterocolitis has been reported in children and adults with acute leukemia (especially acute myeloid leukemia), lymphoma, multiple myeloma, myelodysplastic syndrome, aplastic anemia, AIDS, periodic or drug-induced neutropenia, and immunosuppressive therapy for solid malignant tumors and transplantation. If the patient has no complications, such as perforation or severe bleeding, non-surgical treatment should be administered, including broad-spectrum antibiotics, intravenous versus, parenteral nutrition support, gastrointestinal decompression, and blood transfusion (concentrated red blood cells and fresh frozen plasma as needed). Although surgery is usually avoided in patients with neutropenia and thrombocytopenia, it is recommended if the patient has free perforation or other course of disease that cannot be controlled by other medical procedures or treatment (such as continuous bleeding after correction of coagulation disorders and thrombocytopenia). (Level II recommendation)
4. The antibiotic regimen should be aimed at possible pathogens and pathogens detected in the patient's bloodstream. It should cover Pseudomonas aeruginosa, Escherichia coli, other Gram-negative enterobacteria, and anaerobes. Antifungal drugs should be administered to patients with neutropenia who still have a protracted fever (>72 hours) after the application of broad-spectrum antibiotics. Antifungal drugs that cover fluconazole-resistant candida and Aspergillus are recommended. (Level II recommendation)
5. Antibiotic treatment should be continued until neutrophils return to normal and the symptoms and signs of enterocolitis (fever, abdominal pain, and abdominal tenderness) disappear. Because of the severity of this complication, patients should opt for a dose reduction regimen or change to another chemotherapeutic regimen. (Level II recommendation)
6. Patients with neutropenic enterocolitis complicated with intestinal infection should be detected and monitored during chemotherapy. (Level II recommendation).

CLOSTRIDIUM DIFFICILE INFECTION AFTER CHEMOTHERAPY

Clostridium difficile is an anaerobic spore-producing bacterium that is widely distributed in soil, water, animals, and the intestines of healthy people. The symptoms of CDI range from relatively mild diarrhea to severe life-threatening pseudomembranous colitis, toxic megacolon, and sepsis. The etiology is often associated with the previous use of antibiotics. Age, chemotherapy, and immunosuppression are also risk factors.[¹⁸¹⁹²⁰]

Expert recommendation

1. The general principles for the treatment of CDI include the discontinuation of induced antibiotics and the implementation of infection control measures, including contact protection and hand hygiene. This requires the participation of clinicians, nosocomial infection microbiologists, and nursing staff. (Level I recommendation)
2. First episode: For patients experiencing their first episode of CDI, regardless of the severity, it is recommended to treat them with non-daptomycin instead of vancomycin. For patients with severe CDI, it is necessary to evaluate whether there is an indication for surgery. Judgment of severe CDI includes white blood cell count >15000/μ L and/or serum creatinine ≥1.5 mg/dL and fulminant colitis, hypotension/shock, intestinal obstruction, or megacolon. (Level II recommendation)
3. CDI recurrence means that CDI symptoms subside during appropriate treatment, but reappear within two months after stopping treatment. A regimen containing non-daptomycin instead of vancomycin should be adopted, which can be administered as a standard regimen or an extended intermittent regimen. (Level II recommendation)
4. For patients with three CDIs or subsequent relapses, fecal microbiota transplantation (FMT) is recommended when granulocytes recover and medical conditions permit. For patients who are not eligible for FMT, therapeutic approaches include the same drug treatment used for the secondary recurrence. Oral vancomycin should be used after the treatment. (Level II recommendation)
5. The management of fulminant colitis includes antibiotic treatment and evaluation of surgical indications. The role of FMT in the treatment of fulminant CDI requires further study. Oral vancomycin plus parenteral metronidazole should be used to treat fulminant colitis. When the patient presents with intestinal obstruction, FMT via enema should be performed instead of adding vancomycin via the rectum. However, because of the risk of colon perforation, this operation should only be done for patients who are unresponsive to standard antibiotic treatment, and it should only be performed by personnel with the appropriate professional skills. (Level II recommendation)
6. For patients with an increased risk of CDI recurrence, such as those aged ≥65 years with a history of severe CDI or immunosuppression, oral vancomycin is recommended for secondary prevention if they require continuous systemic antibiotic treatment. It is not recommended to use probiotics to treat or prevent CDI during chemotherapy. (Level II recommendation)
7. As FMT increasingly becomes a standard treatment for recurrent and refractory CDI, FMT centers should establish their own detailed stool bank collection plan and specifications. One of the limiting factors for the wider application of stool bank and FMT programs is the lack of any difference in regulatory standards. FMT may be administered orally through a nasogastric tube, a nasoduodenal tube, or by enema in the form of packaged capsules. (Level II recommendation)
8. The intestinal microecology should be detected and monitored when CDI patients receive chemotherapy again. (Level II recommendation).

CHEMOTHERAPY COMPLICATED WITH CARBAPENEM- RESISTANT ESCHERICHIA COLI OR KLEBSIELLA PNEUMONIAE INFECTION

For nosocomial infection of Gram-negative pathogens, hydrolysis of carbapenems by β-lactamase is an important mechanism of antimicrobial resistance. According to the current sensitivity break point set by the Clinical and Laboratory Standards Institute (and the European Committee on Antibiotic Susceptibility Testing), if Escherichia coli or Klebsiella pneumoniae is obviously resistant to any carbapenem, it should be suspected of carrying carbapenems. The use of broad-spectrum cephalosporins and/or carbapenems is an important risk factor for colonization or infection of carbapenem-producing microorganisms. The incidence of carbapenemase-producing Enterobacteriaceae (CPE) infection is increasing. To control CPE transmission and improve patient outcomes, timely and reliable detection methods and effective antibiotic treatment are needed. For the identification, prevention, and management of CPE-specific infections, it is necessary for all clinically relevant doctors to understand the relevant risk factors, prevention, and management strategies for CPE patients. CPE prevention and management requires infection control practices and facilities. The guidelines need to provide more standardized CPE prevention and management education materials for laboratory personnel, clinical staff, patients, and families. Medical staff must also receive continuous specific education on infection prevention, including special training materials and training time.[²¹²²²³]

Expert recommendation

1. Carbapenemase-producing microorganisms can cause clinical infection or asymptomatic colonization. This group of bacteria can cause a variety of infections, including gastrointestinal infection, bacteremia, ventilator-associated pneumonia, urinary tract infection, and CVC infection. Clinicians should choose antimicrobial therapy according to the results of a drug sensitivity test. In particular, additional drug sensitivity tests should be required for the following drugs: compound preparation of new β-lactams/β-lactamase inhibitors (ceftazidime/abamectin), polymyxin, aztreonam, and tigecycline. (Level II recommendation)
2. For patients with severe infection caused by CPE, the choice of antibiotics depends on the type of carbapenems and the drug sensitivity of the isolates. If hospitalized patients are infected or colonized with carbapenem-producing bacteria, contact protection measures should be adopted throughout the hospitalization. Screening high-risk patients for rectal colonization may also help control transmission. (Level II recommendation)
3. For patients with CPE and mixed intestinal infections, detection and monitoring of the intestinal microecology before, during, and after chemotherapy is recommended. Patients with CPE and mixed intestinal infection are advised to undergo intestinal microecology detection and monitoring before, during, and after chemotherapy again. (Level III recommendation).

HEMATOPOIETIC STEM CELL TRANSPLANTATION-RELATED GASTROINTESTINAL COMPLICATIONS

The intestinal flora of healthy individuals is diverse including the intestinal microecological balance of phylum Firmicutes, phylum Bacteroides, phylum Proteobacteria, phylum Actinomycetes, phylum Verrucomicrobia, and phylum Clostridia. During hematopoietic stem cell transplantation (HSCT), especially in allogeneic hematopoietic stem cell transplantation (allo-HSCT), because of preventive and therapeutic antibiotics, intestinal inflammation, and dietary changes, the diversity of intestinal flora is significantly reduced, which may cause pain, nausea, vomiting, and diarrhea. There are many causes of diarrhea after HSCT, including gastrointestinal mucositis, severe hemocytopenia-related infections, and graft-versus-host disease (GVHD). Treatment depends upon the severity and cause of the diarrhea. There are many reasons for diarrhea after transplantation. Approximately 80% of patients will have at least one acute diarrhea attack within 100 days following allo-HSCT. The evaluation should include quantitative and qualitative stool tests, and even if the volume depletion and metabolic disorders have been corrected, the potential causes should be determined. The assessment is influenced by a number of factors, including the duration of diarrhea and the age of the patient. The following reasons for diarrhea should be considered in this case: Non-oral mucositis resulting from chemotherapy and/or radiotherapy used in the pretreatment regimen can affect the whole gastrointestinal tract, causing diarrhea. Acute GVHD is the most common cause of persistent acute diarrhea after allogeneic HSCT. The common manifestations of gastrointestinal tract involvement include abdominal colic and diarrhea, which consists of a large number of watery diarrhea events at first, and then becoming bloody. Histological examination is helpful for the diagnosis of acute GVHD. Infectious causes after HSCT are also common causes of diarrhea. Infectious bowel disease should be excluded or preventive treatment should be administered at the same time before GVHD is treated with immunosuppressive drug treatment. The common causes of infectious diarrhea include Clostridium difficile, CMV, adenovirus, and enterovirus (e.g., Coxsackie virus, echovirus, rotavirus, norovirus, etc.). A biopsy for intestinal pathological specimens should be performed at the same time. Various virus infections are more likely to occur in high-dose glucocorticoids, T-cell removal, unrelated and related haploidentical transplantations, or cord blood transplantations.[²⁴²⁵²⁶]

Expert recommendation

1. Before HSCT is carried out, the use of chemotherapeutic drugs (pre-treatment regimen) should be discussed in detail by the HSCT MDT, which includes clinicians, nursing team, clinical pharmacists, dieticians, psychologists, to develop a complete pre-treatment chemotherapy prescription and gastrointestinal complication prevention protocol with regular reviews and updates. (Level I recommendation)
2. Oral mucositis is a common complication after transplantation, which usually causes severe pain and affects nutrition intake. Patients receiving myeloablative pretreatment chemotherapy should use oral cold therapy, that is, ice saline gargle for 30 minutes each time, 4–6 times a day. (Level II recommendation)
3. When treating complications of oral mucositis, low-intensity laser irradiation in the oral cavity can be used conditionally. (Level III recommendation)
4. Gastrointestinal mucositis, nausea/vomiting, and ingestion difficulties occur after pretreatment radiotherapy and chemotherapy. It is recommended to evaluate at any time, adopt total parenteral nutrition (TPN) over time when the patient can ingest nutrition through the mouth. The prescription and usage of TPN require the participation of dietitians. (Level II recommendation)
5. The prevention and treatment of nausea and vomiting in patients after HSCT is described in the symptom section. For example, upper gastrointestinal symptoms after allogeneic hematopoietic stem cell donor cell implantation require vigilance for upper gastrointestinal GVHD and after symptomatic and exclusion of infectious factors. Low-dose glucocorticoids (dexamethasone 2.5–5 mg/d for 3–5 days) can be added to observe the improvement of symptoms. (Level II recommendation)
6. Treatment of diarrhea: In addition to the above recommendations on symptoms, the treatment of diarrhea after HSCT should also be combined with the special infection before transplantation and other patient pathogenic bacteria infection in the transplantation ward. This includes CDI and CPE infection, other types of transplantation, the type and time of immunosuppressants after transplantation, the severity of cytopenia, and the time of diarrhea to judge whether there is acute GVHD in the intestine, CMV, or other viral and bacterial infections. (Level I recommendation)
7. Application of FMT in hematopoietic stem cell transplantation: The incidence of CDI during allo-HSCT was between 13 and 30%. Clostridium difficile is an important pathogen to treat with interventional FMT. It primarily occurs in the first month after transplantation; however, the disease is usually mild to moderate in severity and responds well to treatment. There is a lack of data on the potential efficacy of prophylactic FMT in reducing the risk of CDI in C. difficile carriers. FMT prophylaxis is not recommended for this indication. (Level II recommendation)
8. FMT is a potential therapeutic method with application prospects for intractable acute intestinal GVHD. If it is used as early as possible after the restoration of the intestinal mucosal barrier, the mutual influence on infection complications related to extensive immunosuppressive therapy can be avoided. If feasible, systemic antibiotics should be discontinued or replaced with antibiotics of lower activity, such as rifaximin for prevention. This treatment is recommended to be performed 24–48 hours prior to FMT in an experienced transplant unit. (Level II recommendation)
9. In acute GVHD of the gastrointestinal tract after transplantation, if infectious complications occur after the FMT, the intestinal- and blood-borne pathogens should be sequenced and tracked to determine whether they originated from the FMT. (Level III recommendation)
10. Patients with high-risk hematologic neoplasms who have adult acute myeloid leukemia and acute lymphoblastic leukemia and are considered for future HSCT from semi-matched, haploidentical, or unrelated donors are advised to contribute frozen autologous stools in an orderly manner prior to the start of induction chemotherapy if the medical unit has preservation facilities. (Level III recommendation)
11. Based on the high incidence of gastrointestinal complications during HSCT chemotherapy, it is recommended that HSCT patients should undergo intestinal microecology detection and monitoring before and after transplantation in an orderly manner. (Level II recommendation)
12. It is also recommended to perform an intestinal microecology test and evaluation for the recurrence of diseases after HSCT in tumor patients. (Level III recommendation).

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