I. Prevention and treatment of drug-resistant tuberculosis
China is one of the countries with a high burden of drug-resistant tuberculosis, and the World Health Organization estimates that about 1/4-1/5 of multidrug-resistant tuberculosis patients occur in China, and the prevalence of drug-resistant tuberculosis is more serious, and the results of the national baseline survey on tuberculosis drug resistance conducted from 2007 to 2008 showed that the rate of multidrug resistance among tuberculosis patients in China was 8.3%, according to which it is estimated that 120,000 new cases of multidrug-resistant patients occur each year in China Accordingly, it is estimated that China has 120,000 new cases of multidrug-resistant patients each year, accounting for 24.0% of the total number of new cases each year globally, ranking second in the world.
Because the diagnosis of drug-resistant tuberculosis is complex, treatment is difficult, and the course of treatment is often very long, with multidrug-resistant patients generally taking 18-24 months, and the cost of medicine is about 100 times that of treating general patients, so the treatment of drug-resistant tuberculosis causes enormous economic pressure on individuals, families and society.
Classification of the disease
There are four types of drug-resistant tuberculosis, as follows
1, single drug resistance: tuberculosis patients infected with Mycobacterium tuberculosis in vitro is proven to be resistant to a first-line drug anti-tuberculosis drugs.
2. Multi-drug resistance: Mycobacterium tuberculosis infections in TB patients are proven to be resistant to more than one first-line antituberculosis drug, including isoniazid and rifampin, in vitro.
3.Multi-drug resistant (MDR-TB): TB patients infected with Mycobacterium tuberculosis have been shown to be resistant to at least isoniazid and rifampin in vitro.
4.Extensive multidrug resistance (XDR-TB): TB patients infected with Mycobacterium tuberculosis have been shown to be resistant in vitro to any fluoroquinolone antibiotic (e.g., ofloxacin) in addition to at least two major first-line anti-TB drugs, isoniazid and rifampin, and to at least one of three second-line anti-TB injectable drugs (e.g., capreomycin, kanamycin, butamycin, etc.).
Drug-resistant TB can be classified according to whether the patient has been treated with anti-TB drugs and the number of species of anti-TB drugs resistant: primary drug-resistant, initial drug-resistant, acquired drug-resistant, and multidrug-resistant TB.
Primary drug-resistant tuberculosis: refers to the occurrence of drug resistance of Mycobacterium tuberculosis without receiving anti-tuberculosis drug treatment.
2. Initial drug-resistant tuberculosis: refers to mycobacterium tuberculosis drug resistance that occurs after clinical evaluation and is not sufficiently certain that it has not received anti-tuberculosis drug treatment in the past) or treatment for less than 1 month. This includes primary drug resistance and late detection of acquired drug resistance.
3, acquired drug-resistant tuberculosis: refers to drug resistance of Mycobacterium tuberculosis that has been treated with anti-tuberculosis drugs for more than 1 month and occurs.
4. Multidrug-resistant TB (MDR-TB): refers to TB patients who are resistant to at least both rifampin and isoniazid.
III. Causes of morbidity
Drug-resistant TB occurs for several reasons.
1. Irrational treatment regimen: including.
(1) unreasonable and inappropriate combination of drugs;
(2) Inadequate dosage of drugs and inappropriate methods of taking drugs;
(3) Inadequate course of treatment or intermittent medication;
(4) Improper handling of failed and relapsed cases.
2, weak and inadequate TB control measures are important factors in the occurrence of drug-resistant TB, paralysis and blind optimism and poor treatment management cause a large number of TB patients not to be detected, and a significant proportion of TB patients who are detected still do not receive treatment, delayed treatment and irregular treatment.
3, Inappropriate use of second-line anti-tuberculosis drugs and failure to implement strict monitoring and supervision well are important reasons for the formation of drug-resistant TB, especially MDR-TB and XDR-TB.
4, HIV infection and the prevalence and spread of AIDS are accelerators of the emergence and spread of drug-resistant TB.
5, the development of new anti-tuberculosis drugs and the serious lag in the development of drug-resistant TB is also a cause of the formation of drug-resistant TB, because drug-resistant TB can not be cured in a timely manner, and over time the degree of drug resistance is becoming more and more serious, and eventually also produced XDR-TB.
6, other reasons: economic difficulties or adverse drug reactions resulting in intermittent, irregular drug use, poor drug absorption (poor gastrointestinal function), drugs can not fully enter the focal tissue, etc.
There are many causes of drug resistance and multidrug resistance, but they are mainly caused by non-standard treatment of TB. For example, patients do not receive regular treatment and management at specialized tuberculosis control institutions as required, and often stop taking drugs when their symptoms are relieved, and take them again when they have symptoms, as in this cycle, which eventually leads to drug resistance. In addition, patients self-medicate and abuse antimicrobials to cause drug resistance.
Fourth, drug resistance mechanism
Most studies suggest that the occurrence of drug resistance is related to the genetic mutation of Mycobacterium tuberculosis. In general, one or several nucleotide mutations in chromosomal target genes (increase, deletion, substitution) cause nucleotide coding errors resulting in amino acid misalignment, which affects drug binding to the target enzyme and generates drug resistance.
The current research on the mechanism of drug resistance of various TB drugs is still at the stage of continuous exploration, and drug resistance due to mutation of one gene is single gene type resistance, while drug resistance due to mutation of multiple genotypes is multi-gene resistance; it is generally believed that drug resistance to multiple drugs is caused by mutation of different target genes of Mycobacterium tuberculosis one after another. As for the interrelationship between drug resistance genes, it is not known yet, so it can be seen that the drug resistance mechanism is complex, and more problems of drug resistance need to be studied in depth.
V. Clinical manifestations
(I) Multi-prevalent groups
The following groups have a high prevalence of drug-resistant tuberculosis.
1. Patients with failed retreatment or chronic patients;
2. Patients with drug-resistant tuberculosis in contact;
3.Failed primary treatment;
4. Patients with positive sputum at the end of 2 or 3 months of short course chemotherapy;
5, relapse or return patients;
6.Exposure to drug-resistant tuberculosis outbreak or epidemic institutions;
7.Highly endemic areas of drug-resistant tuberculosis;
8. Patients with a history of taking anti-tuberculosis drugs of poor or unknown quality;
All of the above patients should have sputum culture of tuberculosis and drug sensitivity test to determine whether they are drug-resistant patients.
(B) Disease symptoms
The clinical manifestations of drug-resistant tuberculosis are not significantly different from those of common tuberculosis, and the clinical symptoms are diverse and vary in severity, depending on the patient’s age, immune status, nutritional status, coexisting diseases, virulence of the invading Mycobacterium tuberculosis, the amount of bacteria, and the location and severity of the lesion. Clinical manifestations include fever, varying degrees of cough and sputum, hemoptysis in some patients, and respiratory distress when the lesion is extensive. The clinical manifestation of extrapulmonary drug-resistant tuberculosis varies according to the site of disease onset.
(C) Disease risk
Drug-resistant tuberculosis bacteria can be transmitted to healthy people, causing an epidemic of drug-resistant tuberculosis, which not only has a great impact on social public health, but also causes a great psychological and economic burden to individuals and family members due to expensive treatment costs and poor prognosis.
Diagnosis and differentiation
(A) Auxiliary examination
To determine whether a patient with tuberculosis is drug-resistant, a culture of tuberculosis bacteria and drug-susceptibility tests of body fluids such as sputum or pleural fluid, cerebrospinal fluid, and urine are required, and drug-resistant tuberculosis can be diagnosed if the results confirm in vitro resistance to one or more anti-tuberculosis drugs. If the culture is negative and bacteriological resistance results cannot be obtained, a comprehensive judgment of whether treatment is effective and the possibility of drug resistance can be made based on clinical manifestations and imaging and other examination results, and treatment can be carried out according to the drug resistance program as appropriate.
(II) Differential diagnosis
Since patients with non-tuberculous mycobacteria may have clinical manifestations and imaging features similar to those of tuberculosis, and sputum smear of antacid bacilli may be positive, attention should be paid to differentiation. In patients with positive sputum smear, the identification of strains can distinguish between Mycobacterium tuberculosis and nontuberculous mycobacteria while performing roentgenographic culture of Mycobacterium antituberculosis. If it is identified as non-tuberculous mycobacteria (NTM), the DNA sequence of the strain can be further determined to clarify which type of non-tuberculous mycobacteria it is.
VII. Disease treatment
(a) Drug treatment of drug-resistant tuberculosis
1. In the chemotherapy of drug-resistant tuberculosis, WHO classifies anti-tuberculosis drugs into five groups according to their efficacy, experience in use and drug classification.
Group 1 is first-line oral antituberculosis drugs: isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and rifabutin (Rfb);
Group 2, i.e., injectable antituberculosis drugs: kanamycin (Km), butamycarbamycin (Am), capreomycin (Cm), streptomycin (Sm);
Group 3, the fluoroquinolones: Ofloxacin (Ofx), Levofloxacin (Lfx), Moxifloxacin (Mfx);
Group 4: oral antibacterial second-line antituberculosis drugs: ethionamide (Eto), prothiaminamide (Pto), cycloserine (Cs), terizidone (Trd), para-aminosalicylic acid (PAS);
Group 5, i.e., anti-tuberculosis drugs whose efficacy is still uncertain: clofazimine (Cfz), linezolid (Lzd), amoxicillin/clavulanic acid (Amx/Clv), aminothiourea (Thz), imipenem/cilastatin (Ipm/Cln), high-dose isoniazid (H), and clarithromycin (Clr).
Recent findings show that linezolid has a powerful bactericidal effect on Mycobacterium tuberculosis, and clinical use for the treatment of MDR-TB has been effective. Diarylquinolines, nitroimidazolopyrans, diamines, pyrroles, and methiodazine have shown good bactericidal activity against MTB, and some drugs are in clinical trials.
2, the basic principles of chemotherapy for drug-resistant tuberculosis.
(1) Patients with drug-resistant tuberculosis should be diagnosed early and treated promptly.
(2) Design chemotherapy regimens based on the patient’s drug history, the prevalence of drug-resistant MTB strains, and the drugs available.
(3) The chemotherapy regimen should contain at least four core drugs (sensitive drugs in groups 1 to 4 or drugs that have never been used before) that are determined to be effective or almost determined to be effective.
(4) Before the results of the drug sensitivity test are available, the patient should be given the appropriate empirical treatment according to the patient’s type of tuberculosis (I-IV) according to the relevant national norms, and the medication should be adjusted according to the condition after the results of the drug sensitivity test are available. It should be noted that the drug sensitivity test must be of laboratory quality assurance and should have good reproducibility and high reliability.
Isoniazid and rifampicin have the highest accuracy; while E, Z, and S have lower accuracy, and the reliability of group 4 and 5 drugs is not completely sure, therefore, the results of the drug sensitivity test of these drugs cannot completely predict whether the clinical treatment of the drug is effective or ineffective, and may not completely rely on their laboratory results in the actual selection of drugs.
(5) Select drugs in the order of five groups of anti-tuberculosis drugs, and consider selecting drugs from group 5 only when groups 1 to 4 anti-tuberculosis drugs are not sufficient to form an effective chemotherapy regimen for drug-resistant tuberculosis.
(6) Eto/Pto should be preferred for group 4 drugs because of its low cost and efficacy. If cost is not a consideration, PAS should be used first, as its enteric-coated formulation is better tolerated. The combination of Pto/Eto and PAS has a high incidence of gastrointestinal adverse effects, so the combination of these two drugs should only be considered when all drugs in group 4 are needed.
(7) The same class of drugs should not be used in combination, such as injectable antituberculosis drugs, fluoroquinolones, etc.
(8) When unidirectional drug resistance is used, it is important to follow the principle of stepwise administration.
(9) Anti-tuberculosis drugs with incomplete bidirectional cross-resistance, such as rifampicin, rifapentine and rifabutin in the rifam class and Ofx, Lfx and Mfx in the fluoroquinolone class, can be selected from rifapentine and Rfb or Lfx and Mfx when they are resistant to R or Ofx, but the former cannot be used when they are resistant to the latter.
(10) Anti-tuberculosis drugs with complete bidirectional cross-resistance, such as Km and Amk in the aminoglycoside class, Eto and Pto in the thiamine class, and Cs and Trd, should not be used in the same group when either drug is resistant.
(11) Use the full daily dosing method.
(12) Implement full supervised chemotherapy management (DOTS).
(13) Timely detection and management of adverse reactions to anti-tuberculosis drugs.
3. Development of chemotherapy regimens for drug-resistant TB.
Chemotherapy remains the main treatment for drug-resistant TB, and its chemotherapy regimen should be developed comprehensively based on the patient’s drug history, drug resistance, and the prevalence of drug-resistant strains of Mycobacterium tuberculosis in the region.
Mono-resistant TB is often the initial drug-resistant or primary drug-resistant TB, and the standard chemotherapy regimen for primary TB will remain effective. However, because the standard chemotherapy regimen for primary TB at this time has the potential for decreased cure rates or increased relapse, the chemotherapy regimen for mono-resistant TB, especially mono-R, should be appropriately adjusted to minimize the possible risk of treatment failure and development of acquired drug resistance.
The drug resistance profile of multi-drug resistant TB is much more complex than that of mono-resistant TB, with a variety of drug resistance combinations, which can be divided into three basic types: 2-drug resistant, 3-drug resistant, and 4-drug resistant. For these patients, treatment with standard chemotherapy regimens will pose greater risks, and appropriate drug adjustments should be made for various forms of drug resistance combinations to ensure that there are 4 effective or almost effective core drugs in the regimen.
Basic strategies for MDR-TB chemotherapy.
(1) Standardized treatment regimen: This regimen is a set of treatment regimens designed based on representative drug resistance surveillance data and different categories of patients in a particular country or region, with the same regimen used for all patients in the same country (region) or in the same category.
(2) Individualized treatment regimen: This regimen, in turn, is based on each patient’s anti-tuberculosis treatment history and drug sensitivity test results, and varies from patient to patient.
(3) Empirical regimen: This regimen is determined based on each patient’s past drug use history and representative past drug resistance surveillance data from a particular country (region), and can be adjusted based on drug sensitivity test results; this type of regimen is mainly suitable for areas where drug sensitivity tests cannot be performed. This basic strategy is also applicable to other types of drug-resistant TB.
There is a lack of effective chemotherapy regimens for XDR-TB, and measures such as nutritional support, symptom relief, improvement of respiratory function, and control of other pathogenic infections tend to be the mainstay. For low-generation fluoroquinolone resistance and high-generation sensitivity, as well as for injectable antituberculosis drugs in which Amk or Cm are still sensitive or likely to be sensitive, a chemotherapy regimen consisting of two or more drugs from group 5 with inaccurate efficacy can be tried again.
(B) Surgical treatment of drug-resistant tuberculosis
With the increase in MDR-TB in the last decade or so, the number of patients requiring surgical treatment has increased, and the status of surgery in the treatment of drug-resistant tuberculosis, especially MDR-TB, has received a greater degree of attention. For patients with indications for surgery and cardiopulmonary functional reserve sufficient to bear the surgical trauma, surgical excision of the lesion and the cavity where the bacilli are continuously excreted on the basis of adequate chemotherapy (at least 3 months of strong chemotherapy) is of positive significance in eradicating drug-resistant lesions and promoting negative sputum. Postoperative and then aggressive anti-tuberculosis treatment can achieve a cure.
(C) Interventional treatment of drug-resistant tuberculosis
With the widespread use of bronchoscopy in clinical practice, trans-airway interventional therapy guided by bronchoscopy has become an effective treatment method for drug-resistant tuberculosis, especially MDR-TB. In recent years, some scholars have also achieved more satisfactory results in treating MDR-TB by percutaneous pulmonary puncture injection. At present, interventional therapy is gradually becoming an alternative adjuvant treatment for drug-resistant TB, especially MDR-TB.
(D) Other treatments for drug-resistant tuberculosis
1. Immunotherapy
Patients with drug-resistant tuberculosis often have low immune function, especially in severe cases, and improving cellular immune function and the phagocytic ability of phagocytes is of positive significance for the elimination of Mycobacterium tuberculosis. The two most actively researched and mature immune agents are cytokine agents such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2) and Mycobacterium bovis vaccine.
2.Chinese medicine treatment
Chinese medicine can improve the immune function of each TB patient by regulating the body through evidence-based treatment, and improve the patient’s general condition and clinical symptoms, such as hemoptysis, cough, diet, low fever, night sweats, etc., so as to achieve the role of adjuvant treatment of drug-resistant TB.
3.Nutritional support therapy
Drug-resistant tuberculosis can lead to malnutrition, and patients with drug-resistant tuberculosis can be further deteriorated by malnutrition. Therefore, it is necessary to give nutritional support therapy to patients with drug-resistant tuberculosis. For example, vitamins and minerals can be added, and fat emulsions and albumin can be supplemented for those with very poor general condition and severe malnutrition.
In conclusion, the treatment of drug-resistant tuberculosis should be based on chemotherapy as a comprehensive treatment measure in order to achieve the best results.
VIII. Prognosis of disease
Most patients with drug-resistant tuberculosis, mono- and multi-drug-resistant tuberculosis, can be cured with standardized, rational and complete treatment. Patients with multidrug-resistant tuberculosis (MDR-TB) have a relatively low cure rate, but the progression of the disease can be controlled or the lesions can be stabilized under the guidance of a specialist, while patients with extensively drug-resistant tuberculosis (XDR-TB) may have a poor prognosis due to the limited choice of drugs.
IX. Disease prevention
Most drug-resistant TB can be prevented. The key to prevention is to detect patients early and give standardized treatment so that they lose infectivity completely. In addition, to reduce and prevent the spread of drug-resistant TB bacteria, it is recommended that patients with drug-resistant TB, especially those with multidrug-resistant TB, should be hospitalized early. Patients should also consciously pay attention to isolation, preferably wearing a mask when going out, not going to public places where crowds are concentrated, not coughing on people casually, not spitting, etc. Residents should keep air circulation and freshness in their homes, refrain from smoking and alcohol abuse, and exercise properly to improve physical fitness. Newborns should be vaccinated with BCG vaccine, etc.
Hospitals that admit drug-resistant TB need to do a good job of protecting other patients and medical staff, and it is best to set up special wards to strengthen management and reduce or eliminate the spread of drug-resistant bacteria in the hospital. Do a good job of ventilation and cleanliness of the room, and medical staff should be well protected and pay attention to wearing hats and masks.
X. Dietary attention
(A) Disease avoidance
Avoid eating irritating food and things that produce phlegm by fire.
(B) Diet adjustment
Tuberculosis patients should be given high protein and heat energy. Any symptoms of tuberculosis will cause serious depletion of tissue protein and heat energy, so the supply of food protein and heat energy should be higher than normal, the daily supply of protein is 1.5-2.0g/kg, with milk, eggs, animal offal, fish and shrimp, lean meat, soy products and other foods as a source of protein.
Milk is rich in casein and calcium, which is the ideal nutritional food for TB patients. The amount of caloric energy supply is based on the principle of maintaining the patient’s normal body weight, and carbohydrate staple foods can be supplied according to the diet without restriction, but fat should not be eaten more, so as not to cause indigestion and obesity.
At the same time, eat more fresh vegetables and fruits. Vitamins and inorganic salts have a great role in promoting recovery from tuberculosis. Vitamin A has a role in enhancing the body’s ability to resist disease; vitamins B and C can improve the metabolic process in the body, increase appetite, and improve the function of the lungs and blood vessels and other tissues; patients with recurrent hemoptysis should also increase the supply of iron, and eat more green leafy vegetables, fruits and grains, which can supplement a variety of vitamins and minerals.
For patients with drug-related liver disease caused by side effects of anti-tuberculosis drugs, they should be instructed to avoid eating foods with too much heat, such as fried and deep-fried foods and chocolate, to prevent fatty degeneration of the liver and hinder the repair of liver cells. Patients with low food intake should be given intravenous supplementation with appropriate amounts of albumin, amino acids, glucose and vitamins. Since tuberculosis is a chronic infectious disease, while using medication and diet, attention should be paid to adequate rest and appropriate outdoor activities, as well as to the hygiene of the environment and eating utensils.
XI. Disease care
(A) General care
1. Do a good job of disinfection and isolation: Do a good job of isolation of drug-resistant and multi-drug-resistant patients from other patients and health care workers, inform patients not to spit anywhere, cough up sputum in paper for recycling and burning, and cover the mouth and nose with a handkerchief when coughing and sneezing to prevent the spread of drug-resistant and multi-drug-resistant tuberculosis. Therefore, it is important to let family members master the disinfection and isolation methods to protect susceptible people.
2. Correctly retaining sputum specimens: to guide the correct clinical use of drugs.
3.Dietary guidance: rich nutrition plays an important role in the recovery of the disease. Patients should be encouraged to enter a diet with high protein, high calories and high vitamins, such as milk, soy milk, eggs, lean meat, vegetables and fruits. The diet should be as diverse as possible, and no stimulating food.
4, rest, activity guidance: maintain adequate sleep, appropriate activities and exercise. When there is hemoptysis, one should rest in bed and wait for the symptoms to improve significantly before carrying out activities, which should be determined according to the patient’s condition.
(II) Psychological care
Patients with drug-resistant tuberculosis are often treated in isolation because of the infectious nature of the active phase, and are prone to anxiety, depression, feelings of dislike, low self-esteem and suspiciousness. And the treatment course is long, some patients have poor results, often worry about the prognosis of the disease, treatment costs and other issues. The adverse mental and psychological factors affect the treatment and recovery of the disease. Therefore, psychological care should be provided according to the patients’ personality characteristics, so that patients can maintain an optimistic and positive psychology and enhance their confidence in overcoming the disease.
Family members should be instructed to pay attention to the psychological changes of the patient, try to create a warm and relaxed family atmosphere for the patient, and learn more about the prevention and treatment of tuberculosis together with the patient, so that he or she can maintain a positive attitude to life and a good psychological state.
(C) Medication care
The treatment of multidrug-resistant tuberculosis should also adhere to the principles of early, combined, appropriate dosage, regularity, and the whole process. Patients should be informed of the hazards of irregular treatment and the impact on prognosis, so that they can actively accept treatment, cooperate with treatment, regularize treatment, and complete treatment in the future. Patients and their family members should remember to take medication in a standardized manner and follow the doctor’s orders, so that they can take medication on time and according to the dosage, without increasing or decreasing the dosage or the type of medication on their own and without missing the dosage.
For older patients or patients with memory loss, family members should be made fully aware of the therapeutic effects and side effects of the drugs used so that they can monitor the work properly.
Since clinical patients have different tolerance to TB drugs, liver and kidney function, and the presence of multidrug-resistant TB patients, the treatment plan should be individualized, and the adverse effects of drugs should be observed to ensure the completion of rational chemotherapy and to improve the sputum-negative rate of drug-resistant TB.
(IV) Health education
1. Let patients understand the knowledge about drug-resistant and multidrug-resistant tuberculosis, and that only by adhering to the correct treatment principles can they achieve effective treatment results. Let patients actively cooperate, not to stop and change drugs without authorization, to reduce the production of drug-resistant bacteria, and pay attention to the observation of drug adverse reactions.
2, disinfection and isolation guidance: let patients and family members master the handling of sputum and simple and easy to implement disinfection and isolation measures, develop the habit of not spitting, the best to live separately from family members during the period of infection, and try not to go to public places, cough and sneeze with a handkerchief to cover the mouth and nose.
3, pay attention to rest, increase nutrition, reasonable exercise, in order to increase their own resistance and promote recovery.
4. Give good instructions for discharge from the hospital.
12.Expert opinion
1, because of the serious situation of drug-resistant tuberculosis, all patients suspected of drug-resistant tuberculosis should be promptly sputum tuberculosis culture and drug sensitivity test to clarify whether there is drug resistance. It is best to routinely perform sputum culture and drug-sensitive tests on patients with primary drug resistance in units that have the conditions for early detection.
2, drug-resistant tuberculosis, once diagnosed, should go to a specialized hospital for tuberculosis and ask a specialist to develop a reasonable treatment plan based on drug-sensitive results and liver and kidney function, as appropriate.
3, drug-resistant tuberculosis patients should be regular, adhere to the full course of treatment, follow the doctor’s instructions to regularly review and evaluate the efficacy and monitor the adverse drug reactions, in order to achieve the best treatment effect.