Abstract Objective To develop an evidence-based treatment regimen for a patient with multidrug-resistant tuberculosis and to analyze the effectiveness of the regimen. Methods The Cochrane Library (Issue 2, 2007), MEDLINE CD-ROM database (1966 to 2007.7), EMbase database (1984 to 2007.7), Wipu Chinese Science and Technology Journal database (1989 to July 2007), Wanfang database (1997 to 2007.7), Chinese Academic Journals full-text database (1994 to 2007.7) were searched. ～ The Chinese Journal of Tuberculosis and Respiratory Diseases and the Chinese Journal of Anti-Tuberculosis were searched manually, and the literature and guidelines on the control of multidrug-resistant tuberculosis up to July 2007 were screened, and the quality of the literature was assessed and analyzed comprehensively. Results A total of 7 publications were included, of which 3 were clinical guidelines, 1 was a Meta-analysis, and 3 were RCTs. the above-mentioned literature showed that individualized strategies were recommended for the treatment of patients with multidrug-resistant TB who had already used first- and second-line drugs. At least four or more potentially effective antituberculosis drugs are used to form a chemotherapy regimen, with the order of selection determined by drug efficacy. The duration of intensive treatment is determined by the patient’s bacteriologic changes, monitoring of adverse effects, and the antimicrobial efficacy of the drugs comprising the regimen, and the entire course of treatment is at least 18 months after negative sputum mycobacterial cultures. Surgical therapy is an effective adjunctive treatment modality. According to the patient’s condition, the appropriate chemotherapy regimen was developed, and the patient was clinically cured after an intensive period of 6 months and a total course of 22 months. Conclusion Evidence-based treatment of multidrug-resistant tuberculosis can effectively improve the outcome.
1. Case
The patient, male, 35 years old, part-time worker, married, was admitted to the hospital with “recurrent cough, hemoptysis and fever for 3 years, aggravated for 1 month”. 3 years ago, he started to cough and sputum, mostly white mucous sputum, occasionally purulent, and hemoptysis of fresh blood in small amount, about 10-20 ml/day, accompanied by afternoon fever, T 37.5℃~38.5℃, night sweating, emaciation, no hoarseness, chest pain and shortness of breath. chest pain, shortness of breath. He was initially treated with oral cephalosporins and other antibiotics, but was ineffective; 1.5 years ago, he was seen at a local hospital, and was diagnosed with “pulmonary tuberculosis” after checking sputum smear (+), and was referred to the local CDC. The patient was treated with 2HTh1321AO/10 HTh1321O, which was interrupted at times due to gastrointestinal reactions, and the symptoms did not improve after the course of treatment, and the sputum bacteria were not negative. 1 month ago, the above symptoms worsened, and the amount of hemoptysis increased to 50 ml/day, with high fever, T 39℃~39.8℃. He had a history of physical fitness, denied any history of tuberculosis or contact with tuberculosis, smoked for 10 years, 20 cigarettes/day, and had quit smoking since his illness. Examination: T 39℃, chronic disease, right-sided trachea, right thoracic collapse, tube-like breath sounds in the right upper lung, wet rales in the right middle and lower lungs. The heart border is right shifted. Auxiliary examination: chest CT suggested right upper lung destruction, scattered nodules, cavities and patchy shadows in both lungs, and multiple bronchial dissemination foci.
2.Put forward clinical questions
The patient’s diagnosis of multidrug-resistant tuberculosis was clear. The clinical questions formulated according to PICO principles were: 1) the number, type, dose and adverse effects of anti-tuberculosis drugs for patients with multidrug-resistant TB? 2) the optimal anti-tuberculosis regimen for patients with multidrug-resistant TB? 3) the indications for MDR-TB surgical therapy and the timing of surgery? 4) Is interventional therapy effective for MDR-TB? 5) Is immunotherapy effective for MDR-TB?
Translated into answerable questions as follows.
1Patients: multidrug-resistant TB patients, young adults
2 Interventions: anti-tuberculosis drugs, MDR-TB surgery, immunotherapy, interventional therapy
3Outcome indicators: efficacy, adverse effects
3. Evidence search and results
3. 1 Search Cochrane Library (2006, Issue 2), MEDLINE CD-ROM database (1966 ~ 2007.7), Embase database (1984 ~ 2007.7), Wipu Chinese Science and Technology Journal database (1989 ~ July 2007), Wanfang database (1997 ~ 2007.7), Chinese Academic Journals full-text database (1994 ~ 2007.7), and manual search. ～ The Chinese Journal of Tuberculosis and Respiratory Diseases and the Chinese Journal of Anti-Tuberculosis were searched manually for literature and guidelines on the treatment of multidrug-resistant tuberculosis up to July 30, 2007.
3. 2 Search strategy and results
Relevant literature was searched by strength of argument, firstly for clinical guidelines, systematic reviews, Meta-analyses and well-designed large-scale randomized controlled trials (RCTs), and secondly for small-scale RCTs. if neither was available, clinical controlled studies, uncontrolled clinical observations, and expert opinions could be searched in turn. Search terms included: multi-drug resistant tuberculosis; guideline, meta analysis, randomized controlled trial, clinical controlled trial, multidrug resistant tuberculosis, guideline, systematic evaluation, Meta-analysis, randomized controlled trial, and clinical controlled trial. The titles and paper sources were read article by article, and after excluding the same literature from different databases, the abstract or full text was read.
Evidence was classified into 4 levels according to quality as follows: level A for evidence-based practice guidelines, systematic reviews or high-quality Meta-analyses or randomized controlled studies; level B for semi-randomized controlled studies or crossover designs; level C for cohort designs, case-control studies, before-and-after controlled studies and cross-sectional studies, and non-randomized controlled studies; and level D for descriptive studies and expert reviews.
Results A total of 7 papers were included, of which 3 were clinical guidelines [1-3], 1 was a Meta-analysis [4], and 3 RCTs [5-7].
3. 3 Evaluation of the quality of evidence
Three RCTs had a sample size of 130, 72 and 62 cases, respectively, and did not explain the basis of sample estimation; one RCT had a clear explanation of the randomization grouping method and mentioned allocation concealment, one RCT had a less clear explanation of the randomization grouping method and did not mention allocation concealment, and one RCT had a clear explanation of the randomization grouping method but did not mention allocation concealment; two RCTs mentioned baseline comparability One RCT was statistically analyzed for comparability of baseline data, and one RCT did not mention baseline comparability; all had clear inclusion criteria and efficacy assessment indexes, but only intermediate indexes (sputum bacteria and imaging results) were observed in three RCTs; all three RCTs were statistically processed, and two of them provided statistical methods; two RCTs mentioned missed visits, and one did not.
4. Study results
4.1 Choice of MDR-TB combination chemotherapy regimen
The WHO guidelines for the treatment of multidrug-resistant TB [1] state that standardized, empirical or individualized treatment strategies can be used. In the same patient, a combination of both strategies can be used. In areas where second-line drugs are widely used and drug-sensitivity testing is available, the use of individualized strategies can avoid the use of ineffective and highly toxic and expensive drugs. Use at least four or more potentially effective antituberculosis drugs containing drugs from groups 1-5 (group 1 for all first-line drugs, group 2 for aminoglycoside injectables, group 3 for quinolones, group 4 for second-line oral drugs including propylthiouracil, cycloserine, and para-aminosalicylic acid, and group 5 for potentially effective drugs including clofazimine, amoxicillin clavulanate potassium, clarithromycin, and linezolid), in the order of potency The order of selection was determined by the grade of potency. Be careful not to use drugs that are cross-resistant to known resistant drugs and reduce the use of drugs with poor safety profiles. Increased doses of isoniazid may benefit patients even if they are resistant to isoniazid. Be prepared to prevent, detect, and manage adverse reactions (especially allergic reactions, hepatic and renal toxicity, ototoxicity, and psychiatric symptoms). The guidelines specifically mention that aminoglycosides can be tapered (three injections per week) during the intensive phase if adverse reactions occur.The Caminero clinical guidelines [2] recommend the use of individualized treatment strategies for patients with MDR-TB who have already been treated with first- and second-line agents. Chemotherapy regimens consisting of 4 and more sensitive drugs are recommended.
The only Meta-analysis [4] noted that the search and analysis did not reveal a superior combination chemotherapy regimen. 1 RCT [5] (n=130) evaluated the efficacy and safety of regimens containing rifapentine (dosage 0.3 qd) or rifabutin (dosage 0.6 biw) in patients with multidrug-resistant tuberculosis over a period of 18 months. The negative rates of sputum smear and sputum Mycobacterium tuberculosis culture were found to be 75.00% and 65.08% in the test and control groups, respectively, and the rate of lesion visualization was 46.15% and 44.62% in the two groups, respectively, with no statistically significant difference. One RCT [6] (n=72) evaluated the recent efficacy of a combination chemotherapy regimen containing amoxicillin clavulanate potassium (domestic 2.4g 2/day or imported 1.8g 2/day IV and 375mg 3/day orally) in patients with multidrug-resistant pulmonary tuberculosis for 6 months, and found that the sputum-negative rate in the test group with amoxicillin clavulanate potassium was 57.1% compared with 33.1% in the control group. One RCT [7] (n = 62) evaluated the efficacy and safety of a chemotherapy regimen containing Lycopodium (0.3 3/day) in patients with multidrug-resistant tuberculosis for 9 months, and the results were 61.0% and 65.0% in the test group for Tu-Yang and Pei-Yang, respectively. The rates of sputum reversion in the test group and control group were 5% and 20% after 2 years, respectively. The main adverse reactions in the test group and the control group were gastrointestinal reactions and mild liver function damage, and there was no statistical difference between the two groups.
4.2 MDR-TB chemotherapy regimen
WHO guidelines for the treatment of multidrug-resistant tuberculosis [1] state that the intensive phase (with injectables) should be at least 6 months or 4 months after negative sputum; the entire course of treatment should be at least 18 months after negative sputum mycobacterial cultures and can be extended to 24 months after negative cultures. With regard to the duration of the intensive phase, the Caminero guidelines [2] comment that the WHO, ATS, and BTS guidelines and their numerous expert opinions vary from the shortest recommendation of 2 months to the longest requiring the use of injectables throughout. The guidelines recommend deciding the duration of the intensive period based on the patient’s bacteriological changes, monitoring of adverse reactions, and the antimicrobial efficacy of the drugs comprising the regimen. If the regimen has three or more effective drugs belonging to groups 1, 2, or 4 after withdrawal of the injectable, the intensive period can be extended until the sputum bacteria are negative; if any one of the three effective drugs belongs to group 5 after withdrawal of the injectable, the intensive period must be extended. Our “Opinion on Chemotherapy of Multidrug Resistant Tuberculosis” [3] states that the course of treatment is sputum-negative or at least 18 months of the same treatment continued after surgery.
4.3 Choice of surgical therapy for MDR-TB
Although no high-quality RCT evidence is available, two foreign guidelines [1,2] recommend surgical therapy as an adjunct to the treatment of MDR-TB. the WHO (2006) guidelines recommend [1] indications for persistent positive sputum bacteria, multi-drug resistance, and limited lesions. Surgery is required early in the disease after at least 2 months of chemotherapy, and the procedure is usually chosen as pneumonectomy, after which chemotherapy should be continued for 12-24 months. the Caminero guidelines [2] recommend that surgery be considered when the following three conditions are met: 1) the lesion is limited; 2) lung function can tolerate surgery; and 3) there is a lack of sufficiently effective drugs to form a chemotherapy regimen to cure the patient. The timing of surgery is best chosen at the time of sputum negativity, and postoperative adherence to a well-defined 18-24 month chemotherapy regimen is mandatory.
4.4 Choice of interventional therapy for MDR-TB
No high-quality clinical evidence was retrieved.
4.5 Choice of MDR-TB immunotherapy
High-quality clinical evidence was not retrieved.
5. Evaluation of the applicability of the evidence
Based on the above high-quality clinical evidence, use empirical treatment followed by individualized treatment strategy (i.e., first develop a chemotherapy regimen based on the patient’s chemotherapy history, and then adjust the medication based on drug sensitivity testing). At least four or more potentially effective anti-tuberculosis drugs were used, taking into account the patient’s past drug history, the occurrence of adverse effects, the local drug supply, and the patient’s affordability. The patient had extensive lesions, so surgical treatment was not considered. Interventional and immunotherapy were not used.
6. Evidence-based treatment plan for the patient
After 2 months, sputum culture results showed the growth of human type Mycobacterium tuberculosis, which was resistant to H, R, Z, E, S, A, Th1321, O, and sensitive to CPM and PAS. Since CPM and PAS were used, the drug was continued and the regimen was not adjusted. The injection CPM was changed to 3 times a week after 3 months of daily intravenous use and discontinued after 3 months of use; and H and PAS were changed to D 0.3 tid after 3 months of chemotherapy. the total course of treatment was 22 months.
7.After-effect evaluation
The patient had no further fever, cough and hemoptysis were significantly reduced after 3 months of medication. No serious complications such as respiratory failure and pulmonary heart disease occurred. The sputum culture was negative after 4 months of medication. At the end of the course of treatment, a repeat chest CT showed significant resorption of the lesion. No abnormality was found in blood routine, liver and kidney function, electrolytes and electrocardiogram.