Study design
This study is an open-label, prospective cohort study. All patients received treatment for 18 months. They were followed up for at least one year after end of the course. The trial was mainly conducted at a national TB clinical treatment center with nearly 300 beds receiving referral of patients with MDR-TB from eastern China. In addition, the hospital is the only specialized hospital receiving MDR-TB in Shanghai and undertakes the region formulation and management collaborated with Center for Disease Control and Prevention （CDC）.
Study patients
From January 2017 to January 2018， we enrolled patients between 18 and 65 years diagnosed as MDR-TB confirmed by BACTEC MGIT 960 liquid culture（MGIT 960） and Minimum Inhibitory Concentration（MIC）DST referred from 3 TB specialist hospitals and shanghai CDC.
Inclusion criteria were to include MDR-TB patients confirmed by MIC DST at least resistant to INH at low concentration and rifampicin (R) resistance within 2 months prior to screening; and patients had no injectable agents or FQs resistance; patients previously only received first-line anti-TB treatment (ATT) or had no previous history of ATT or previous history of second-line ATT less than one month.
Excluded criteria were as follows: XDR-TB patients (resistant to both flquinolones and second-line injection drugs) or pre-XDR (resistant to either flquinolones or second-line injection drugs); patients had poor compliance to any drugs within the regimens; any serious systemic disease or disease of the immune system; coexisted with extrapulmonary tuberculosis; co-infected with HIV and other virus, taking immunosuppressive agents; history of flquinolone use for more than one month in the recent 6 months; pregnant.
We defined the newly diagnosis of MDR-TB as having never been treated for TB or less than one month of treatment history (9); Re-treated cases were defined as registered MDR-TB patients who had previously taken first-line anti-TB drugs for more than one month at the time of history inquiry; or if there is sufficient documentary evidence of having been treated with first-line anti-TB drugs for one month or more in the past.(10)
Inclusion and intervention
Patients satisfied with included criteria were administered by the regimen including Amikacin (Ak), Fluoroquinolones（FQs）, Cycloserine(Cs), Protionamide (Pto), Pyrazinamide (PZA) and Pasiniazine (Pa) for six months with injectable Ak followed by 12 months of oral FQs, Cs, Pto, PZA and Pa.
All patients were screened within one week of receiving the first dose and administered under directly observed therapy (DOT) throughout the treatment course. During the course of treatment, patients were visited by the same specialist every two weeks until the end of the course. Visits were made every 3 months after completion of treatment until 12 months after completion of treatment.
Microbiological assessment
Sputum/bronchoalveolar lavage samples were collected for smear microscopy and MTB culture at the following times: at baseline; Follow-up was followed up at 1, 2, and 3 months, and then once every 3 months until the end of the course.
All MTB positive isolates were transferred to the TB basic laboratory for the determination of MIC were 1µg/mL for Pa , 5µg/mL for Ak，1µg/mL for Rifampicin（R）, 0.2 µg/mL for INH, 0.5µg/mL for Mfx and 1µg/mL for Lfx,.
Treatment efficacy evaluation
Treatment outcomes for MDR-TB were evaluated according to WHO guidelines (11). The patients were examined by Chest CT imaging every three months and sputum culture once a month during the treatment period.
The treatment outcomes were divided into “cured”、“completed treatment”、“failure”、“default”and “death”. The “cured” was referred as patients completed treatment with consistently at least five negative culture results for the final 12 months of the treatment course and without evidence of treatment failure(12); Completed treatment was determined by bacterial negative conversion at the end of the treatment with less than three negative cultures. The ‘‘failure’’ was referred as patients had sputum culture positive in the final 12 months of the treatment course or if any one of the final three cultures was positive or to be discontinued due to clinical or radiological adverse reactions or adverse events. ‘‘Death’’ was patients died from any reason during the course of ATT; ‘‘Default’’ was referred as patients whose TB treatment was interrupted for at least two consecutive months for any reason. Favorable treatment outcomes were defined as sum of cured and treatment completed , unfavorable outcomes included “failure”, “default” and “death”(13).
Safety assessment
Included patients were monitored by blood and urine routine, liver function, renal function at least once a months, hearing test once a month, followed at outpatients department of TB by physicians once a moths or less if possible. Adverse events（AEs）endpoints included all-cause mortality and incidence of adverse events that occurred or worsened during treatment, defined by the Division of Microbiology and Infectious Diseases(14). And the severity of AEs according to whether they were determined by researchers to be related to the drug in question.
Statistical analysis
Statistical analysis was used SPSS 18.0 (IBM Corp, Armonk, NY, USA). Categorical variables such as treatment outcome, sputum conversion rate were analysed using X2 tests and Fisher’s exact tests, and continuous variables were analysed using independent t-tests and Mann-Whitney U-tests. P value < 0.05 was considered statistically significant.