Bone and joint tuberculosis is a clinical disease caused by Mycobacterium tuberculosis infection in bone and joint. (1) Early detection and early treatment are still of great importance. Once diagnosed, regardless of whether the patient is in the initial stage or in the recurrent treatment, treatment should be carried out as early as possible so as to “detect and treat”. (2) Regularity The key to successful chemotherapy is to adhere to regular drug use within the prescribed time according to the prescribed protocol. It is important to comply with the drug dose, route of administration, and time and interval of drug administration as stipulated in the chemotherapy protocol to avoid omission or interruption of drug administration. Li Yuanda reported that there are more reasons for recurrence of osteoarticular tuberculosis after surgery, of which irregular chemotherapy accounts for 32.5%. (3) The whole process Ensuring the completion of the course of treatment prescribed by the program is a prerequisite for ensuring the efficacy of treatment. Do not stop the treatment early, otherwise it will increase the failure rate and recurrence rate of treatment. To achieve “complete treatment”. (4) Appropriate dosage refers to the dosage of each anti-tuberculosis drug that has the best effect without or with few adverse effects. If the dose is too small, the reproduction of tuberculosis bacteria cannot be inhibited. If the dose is too small, it cannot inhibit the reproduction of tuberculosis bacilli, and it is easy to produce drug resistance and affect the efficacy; if the dose is too large, it is easy to produce side effects. (5) Combination Combination of drugs is the main principle of chemotherapy. Using 2 or more drugs at the same time can increase the synergistic effect of drugs to enhance the efficacy and reduce the occurrence of secondary drug-resistant bacteria. Shi Jiandang, Department of Spinal Orthopedics, General Hospital of Ningxia Medical University
(I) Anti-tuberculosis drugs
The blood and intracellular drug concentrations can only play a bactericidal role when they reach more than 10 times the minimum inhibitory concentration (MIC) in the test tube at conventional doses, otherwise they can only play a bacteriostatic role. Streptomycin and pyrazinamide are also bactericidal agents, but they can only be considered half bactericidal agents, because streptomycin can only have its maximum effect in alkaline environment and is not effective against intracellular bacteria, while pyrazinamide can penetrate into phagocytic cells and can only have its maximum effect in acidic environment. Ethambutol, para-aminosalicylic acid, and aminothiourea are all bacteriostatic agents. The mechanism of bacterium production and major adverse effects of commonly used anti-tuberculosis drugs are shown in Table 1, and the doses of major anti-tuberculosis drugs are shown in Table 2.
Table 1 Commonly used anti-tuberculosis drugs bacteriocidal mechanism and major adverse reactions
Drug
Abbreviation
Bactericidal mechanism of action
Major adverse effects
Isoniazid
Rifampicin
Streptomycin
Pyrazinamide
Ethambutol
p-Aminosalicylic acid
H, INH
R, RFP
S, SM
Z, PZA
E, EMB
P, PA
DNA synthesis
mRNA synthesis
Protein synthesis
Pyrazinic acid inhibition
RNA synthesis
Intermediate metabolism
Occasional hepatic impairment, peripheral neuritis
Hepatic impairment, allergic reactions
Hearing impairment, vertigo, renal impairment
Gastrointestinal discomfort, hepatic impairment, uric acidemia
Optic neuritis, arthralgia
Gastrointestinal discomfort, allergic reactions
Table 2 Doses of major anti-tuberculosis drugs
Drug name
Adult daily dose (g)
Children’s daily dose (mg/kg)
Intermittent therapy daily dose (g)
Isoniazid
0.3-0.4
(5-8mg/kg)
10-15
0.6-0.8
Rifampicin
0.45-0.60
(8-10mg/kg)
10-20
0.6-0.9
Pyrazinamide
1.5-2.0
(20-30mg/kg)
20-30
2.5
Ethambutol
0.75-1.0
(15mg/kg)
1.5
Streptomycin
0.75-1.0
(15-20mg/kg)
15-30
0.75-1.0
(II) Development and selection of chemotherapy regimen
According to the condition and morbidity of tuberculosis patients, comprehensive analysis will be made to determine the cases of primary treatment, re-treatment, relapse and drug resistance, and the corresponding tuberculosis drug regimen will be given, adhering to the principle of “early, combined, appropriate, regular and full use of sensitive drugs”, with at least 2-3 types of bactericidal drugs (H/R/S/Z) at the same time. For combined with other diseases (liver and kidney impairment, diabetes mellitus, poor hematopoietic function or immune diseases, etc.), use cautiously or choose anti-tuberculosis drugs with low toxicity, and increase the duration of drug use appropriately.
1. Commonly used regimen The best chemotherapy regimen should meet the following conditions: (1) the best drug combination: it should consist of a combination of bactericidal drugs, sterilizing drugs and drugs to prevent drug resistance; (2) it must follow the prescribed drug type, dose, number of doses and sufficient duration of treatment; (3) high efficacy, low toxicity, easy to be accepted by patients and widely implemented.
(1) Long course chemotherapy (standard chemotherapy) INH+PAS with SM for the first 3 months and a full course of 1.5 years. 1950s British Medical Research Council (BMRC) summarized the efficacy of standard chemotherapy for osteoarticular tuberculosis in several articles, with a cure rate of 89%, a relapse rate of 3% and a mortality rate of 1.4%. The efficacy of this chemotherapy regimen has been confirmed by domestic and foreign scholars.
(2) Short-course chemotherapy regimen Formulation principles: chemotherapy should be highly effective, sensitive, less toxic and economical. Isoniazid and rifampicin are the most basic drugs, which are indispensable, and pyrazinamide and other drugs are added to prevent recurrence by sterilizing and sterilizing the A, B and C flora, which constitute the standard short course chemotherapy regimen, and all drugs should be taken once in the morning before meals. In recent years, there are more short-course chemotherapy regimens for osteoarticular tuberculosis, as detailed in Table 3.
Table 3: Common short-course chemotherapy regimens for osteoarthritic tuberculosis
Chemotherapy regimen
Surgery
Observation (month)
Recurrence rate
Authors
6RH (initial two months SMqd)
6EH (initial two months SMqd)
6RH
6RH
9RH
6RH+S/2/week
9RH+S/2/week
4SHRE/5HRE
4SHRE/5H3R3E3
6RH
9RH
2SHRZ/6H3R3T1
2SHRZ/5H3R3T1
6HRZ
×
×
√
×
×
√
√
×
×
√
√ √ √
60
60
60
60
60
1.08%
1.15%
3.26%
1.04%
92%*
Hannachi(1997)
Hannachi(1997)
MADRAS(1983)
MADRAS(1983)
MADRAS(1983)
MADRAS(1986)
MADRAS(1986)
Domestic Collaborative Group
National Collaborative Group
Griffiths
Griffiths
National Collaborative Group
National Collaborative Group
Loenhout-Rooyacher (2002)
Note: √ is surgery, × is drug alone; * is efficiency
There are three main drugs for short-course chemotherapy: TNF, RFP, and PZA. the combination of the three drugs can exert their respective effects and synergistic effects. For example, INH has the strongest bactericidal effect on metabolizing flora, RFP is most effective on intermittent metabolizing flora; PZA plays a special role on intracellular flora in acidic environment. And INH and RFP are the best combination to prevent drug resistance, which can greatly shorten the course of treatment.
(3) Ultra-short course chemotherapy regimen The chemotherapy regimen is 4.5HRZ, which is recommended by the National TB Short Course Chemotherapy Collaborative Group. The intensive period is 2 months, followed by the consolidation period, and the duration of treatment is 4.5 months. In the chemotherapy of pulmonary tuberculosis, any chemotherapy regimen less than six months is an ultra-short-course chemotherapy regimen, which has been internationally recognized to be more effective in the chemotherapy of pulmonary tuberculosis. Based on the theoretical basis of ultra-short course chemotherapy and clinical research, it is inferred that ultra-short course chemotherapy is not only feasible in osteoarthritic tuberculosis, but also should be more effective than pulmonary tuberculosis. (1) The treatment of osteoarticular tuberculosis is more surgical than pulmonary tuberculosis, and surgical treatment removes the tuberculosis lesions, and drugs are more likely to control the lesions. (2) Osteoarticular tuberculosis is a type of extrapulmonary tuberculosis, and prospective controlled studies have shown that the effect of short-course chemotherapy for almost all extrapulmonary tuberculosis is similar to that of pulmonary tuberculosis. (3) Short-course chemotherapy for 6 months has shown good results in the treatment of osteoarthritic tuberculosis. (4) Ultra-short-course chemotherapy of 4.5-5.5 months is feasible in pulmonary tuberculosis, so it should be feasible in osteoarthritic tuberculosis. The orthopedic department of the General Hospital of Ningxia Medical University has conducted a study on this, and the results showed that the treatment effect is not different from standard treatment and short-course chemotherapy, but long-term follow-up of a large sample is still needed.
2. Selection of chemotherapy regimen
(1) Treatment of primary osteoarticular tuberculosis Primary osteoarticular tuberculosis refers to: (1) patients who have not yet started anti-tuberculosis treatment; (2) patients who are on standard chemotherapy regimen but have not completed the course of treatment; and (3) patients who have been on irregular chemotherapy for less than 3 months. For the treatment of primary osteoarticular tuberculosis, WHO recommends the standard chemotherapy regimen, and patients with mild symptoms can be treated by deleting streptomycin during the intensive phase, and increasing the duration of the consolidation phase for those with slow results. In recent years, short-course chemotherapy regimens have been used for the treatment of primary osteoarthritic tuberculosis, and the treatment regimen has been adjusted according to the treatment effect, i.e., a variable short-course chemotherapy regimen, and after the intensive period, the consolidation period is extended appropriately according to the disease, for example, the 4SHRE/5HRE regimen is changed to 4SHRE/XHRE, with X indicating the extended month.
(2) Treatment of retreatment osteoarticular tuberculosis Retreatment osteoarticular tuberculosis refers to (i) patients who have failed conservative treatment; (ii) patients with recurrence of local lesions after surgery; and (iii) patients who have been treated with irregular chemotherapy for more than 3 months. The chemotherapy regimen is based on H/R(T)/E/Z(TH)/S(KM)/O, and is adjusted several times according to the treatment effect and drug sensitivity test results.
(3) Treatment of drug-resistant osteoarthritis [6,7] The chemotherapy regimen for drug-resistant and multidrug-resistant osteoarthritis advocates the use of drugs based on drug sensitivity results, and the course of treatment should be extended to 24 months, and WHO recommends that first-line and second-line antituberculosis drugs can be mixed. First-line drugs can still be used according to drug sensitivity; ①SM can be used for 3-5 months in the intensive phase, and EMB is commonly used as a substitute for the elderly and for inconvenient injections, but due to its reduced application, there are fewer cases of SM resistance than INH/RFP. ②PZA is mostly used in the intensive phase of standard short course chemotherapy, so resistance to the drug may be low in frequency and is now often used. ③EMB: The antimicrobial effect is similar to that of SM, and it is also the first choice of commonly used drugs. Second-line anti-tuberculosis drugs are mostly the main drug for the treatment of drug-resistant osteoarticular tuberculosis. Sodium para-aminosalicylate is a bacteriostatic agent and is used to prevent drug resistance to other drugs. Some of the INH-resistant strains are sensitive to isoniazid para-aminosalicylate. Regimen without drug sensitivity results: 3TH,S(KM/AM)ZO/18THO; for H/R resistant: 3-6THOEZAK(SM/AM)/18THOE; for H,R,S,E resistant: 3-6THOZKM(AK)/18THOCS.
(iii) Problems noted in chemotherapy treatment
1. Anti-tuberculosis drug toxic side effects and treatment can be divided into allergic reactions and drug toxicity reactions. (1) The frequency of allergic reactions accounts for the first place of side effects (about 60%), and the majority of serious side effects are caused by rifamycins, which occur mostly within 1-2 months after taking the drugs. Multiple drug allergic patients, regardless of the severity of the reaction, the principle of quick discontinuation and early desensitization, after determining the allergen, to use less than 1/10 of the usual amount of desensitization, and the development of emergency treatment measures, serious allergic patients should not be repeated to verify. Those in anaphylactic shock should be resuscitated according to shock. Almost all anti-tuberculosis drugs can cause rash, commonly caused by INH, SM, PAS, etc. Scarlet fever-like, eczema-like and purpura-like rash, and severe cases can cause exfoliative dermatitis. There should be symptomatic treatment with anti-allergy and anti-itch drugs. (2) SM, KM and CP have certain toxicity to hearing and vestibule, and should not be used in elderly patients with renal impairment and hearing impairment as far as possible; Tb1 causes leukopenia and hemolytic anemia, PZA can cause joint pain, EMB can cause visual impairment, OFLX affects bones, and should not be used in developing children; drug-related liver injury is the most common serious adverse reaction in the course of anti-tuberculosis treatment, especially those containing Rifampicin, isoniazid, and pyrazinamide regimens are particularly common. In order to reduce the damage to liver function caused by anti-tuberculosis drugs and to ensure the success of chemotherapy regimens, we believe that: 1) careful medical history must be taken before starting chemotherapy; patients with hepatitis B virus, alcoholism and schistosomiasis are prone to liver function damage. It is best to include liver function and HBVM in the routine examination before chemotherapy for tuberculosis. ②Patients with elevated ALT but not more than 200U during chemotherapy should continue chemotherapy under close observation; if ALT is elevated or reduced, and AST is elevated more than 3 times the normal value, discontinuation should be considered; patients with ALT and AST exceeding 150U at the same time and without clinical symptoms should terminate anti-tuberculosis treatment. ③Patients with a single AST elevation of 100 U or more during chemotherapy should have their liver function rechecked at an interval of about 7 d to consider the next step of treatment. ④Liver function should be checked promptly when gastrointestinal symptoms appear during chemotherapy, and anti-tuberculosis should be suspended for patients with elevated ALT and accompanying gastrointestinal symptoms or jaundice. ⑤ HBVM-positive patients should have their liver function checked regularly, and those with major or minor triplets without other diseases can be included in the scope of chemotherapy.
2. Pay attention to the time limit of preoperative and postoperative chemotherapy How much preoperative anti-tuberculosis chemotherapy is appropriate for patients who need surgical treatment, we believe that it should be classified and treated differently. (1) Patients with good general condition, only patients with simple osteoarticular tuberculosis, no or mild tuberculosis toxicity, good nutritional status, and good function of important organs, can be operated in 2-3 weeks of anti-tuberculosis drug treatment. (2) Patients with poor systemic condition, combined with other parts of tuberculosis, obvious manifestations of tuberculosis poisoning, poor nutritional status, and important organ dysfunction, the preoperative medication time should be longer, about 4-6 weeks. (3) For patients with severe manifestations of systemic tuberculosis intoxication or combined with cornified pulmonary tuberculosis, the preoperative medication time should be more than 6 weeks. In addition, the preoperative medication time depends on the treatment effect, and the patient’s systemic condition improves after systemic supportive therapy and anti-tuberculosis medication. Pre-operative preparation should be based on the principle that the patient can tolerate the surgery. If the paraplegia worsens during the anti-tuberculosis treatment, emergency surgery should be performed to release the nerve compression and restore the function. Perioperative H and R drugs should preferably be administered intravenously to improve patient compliance and reduce gastrointestinal side effects. Postoperative anti-tuberculosis drug treatment involves the selection of the overall chemotherapy regimen, regardless of which chemotherapy regimen is chosen, it must be implemented according to the principles and methods of chemotherapy. Before discontinuing postoperative chemotherapy, the following must be achieved: normalization of general condition, disappearance of abscess, sinus tract, dead bone and cavity, close mosaic of bone graft interface, no resorption of bone graft or signs of healing, secure internal fixation, and normalization of ESR and CPR.
3. Pay attention to the application of DOTS strategy in patients with osteoarticular tuberculosis and improve the compliance of patients with osteoarticular tuberculosis with medication. The management of chemotherapy for patients is one of the key aspects of treatment success or failure. Only when patients adhere to regular medication and complete the prescribed course of treatment can they achieve the goals of curing the disease, eliminating the source of infection and interrupting the epidemic, and protecting the healthy population. Directly observed treatment, short course (DOTS) strategy is the current WHO recommended strategy for global TB control. The patient’s family members who can take real responsibility can also perform the treatment at home. Health care providers should focus on strengthening health education for patients and their families to make them aware of the importance of taking medication regularly and throughout the course of treatment, and to improve compliance with medication in patients with osteoarthritis.
In conclusion, anti-tuberculosis drug therapy for osteoarticular tuberculosis plays a decisive role in the cure of osteoarticular tuberculosis patients, and individualized chemotherapy regimens should be developed according to each patient’s specific situation. The cure rate of osteoarticular tuberculosis is improved by combining nutritional support, immune enhancement and surgery.