Abstract
Objective
The aim of the study was to analyse the characteristics of rifampicin-resistant tuberculosis patients in Spain.
Methods
This was an ambispective observational study of a multicentre cohort of patients diagnosed between January 2019 and July 2023 in most Autonomous Communities (retrospective period 2019–2020, prospective 2021–2023).
Results
94 patients were included; 83 (88.3%) had pulmonary tuberculosis. The mean age was 38.00±17.8 years; 67 (71.3%) were male, 62 (66.0%) were from countries other than Spain, six (6.4%) were HIV-infected and 24 (25.5%) had previously treated tuberculosis. Nine patients had rifampicin-resistant tuberculosis (RR-TB), 75 multidrug-resistant tuberculosis (MDR-TB), nine pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and one XDR-TB. Treatment included bedaquiline in 39 (41.5%) patients, linezolid in 87 (92.6%), fluoroquinolones in 82 (87.2%), clofazimine in 64 (68.0%) and delamanid in 27 (28.7%). Treatment was supervised by experts in 63 cases (67.0%). In 43 patients (45.7%), there were difficulties obtaining authorisation for drug prescription (bedaquiline or delamanid). 21 patients (22.3%) had difficulties understanding the treatment. The final treatment outcomes were cured in 60 cases (63.8%), treatment completed in 23 (24.5%), deaths in 3 (3.2%), with 2 due to tuberculosis, loss to follow-up in five (5.3%) and not evaluated in three (3.2%). No treatment failures occurred. Successful outcomes were achieved in 83 patients (88.3%). MDR-TB compared with pre-XDR-TB (OR 8.77, 95% CI 1.42–45.55; p=0.01) and no treatment comprehension difficulties (OR 10.61, 95% CI 2.78–40.48; p=0.001) were both associated with successful outcomes.
Conclusions
Most patients achieved successful outcomes with individualised regimens guided predominantly by experts. Patients with pre-XDR-TB and those with comprehension difficulties had significantly reduced success rates.
Shareable abstract
In a cohort of 94 patients diagnosed with rifampicin-resistant tuberculosis in Spain, a high treatment success rate (88.3%) was achieved using individualised regimens guided by experts, despite problems with prescribing bedaquiline and delamanid https://bit.ly/3UCgKiA
Introduction
Tuberculosis caused by Mycobacterium tuberculosis resistant to rifampicin has become a major barrier to the elimination of this disease [1]. According to the latest definitions established by the WHO [2, 3], this includes tuberculosis with at least rifampicin resistance (RR-TB), tuberculosis with resistance to at least rifampicin and isoniazid (MDR-TB, from “multidrug-resistant tuberculosis”), using the term RR/MDR-TB to encompass both, as well as pre-XDR-TB from “pre-extensively drug-resistant tuberculosis” (RR/MDR-TB plus additional resistance to any fluoroquinolone) and XDR-TB, from “extensively drug-resistant tuberculosis” (RR/MDR-TB plus resistance to any fluoroquinolone and at least one of the other drugs included in the WHO's Group A [4, 5], currently referring to resistance to linezolid, bedaquiline or both).
According to the WHO's 2024 annual global tuberculosis report [6], an estimated 10.8 million cases occurred in 2023. Regarding RR/MDR-TB, the report estimates 400 000 cases, with five countries accounting for over half of the patients: India (27%), the Russian Federation (7.4%), Indonesia (7.4%), China (7.3%) and the Philippines (7.2%).
Data on the number of diagnosed RR/MDR-TB patients in Spain are available from published studies [7, 8] and epidemiological reports from the National Epidemiological Surveillance Network (RENAVE) [9]. The situation is more favourable compared with the global scenario, with a primary RR-MDR-TB proportion of 1.2 % among native-born individuals and 3.4 % among foreign-born [7]. The annual number of cases is relatively low compared with other countries in Europe and worldwide, as showed in a paper by the Spanish MDR-TB Working Group, which reported 834 cases diagnosed over 20 years, with a fairly consistent annual distribution [8]. However, data remain scarce, and no cohort studies on RR/MDR-TB in Spain have been published, particularly regarding treatment, follow-up and final classification. Therefore, we believe our study results could complement the epidemiological data provided by RENAVE [9] and reports from the WHO and European Centre for Disease Prevention and Control (ECDC) concerning Spain [10–11].
In Spain, tuberculosis diagnosis and treatment are integrated into the National Health System and follow national and WHO guidelines. Molecular tests (e.g. Xpert MTB/RIF and line probe assays) and drug susceptibility testing (DST) are routinely recommended. Laboratories operate within a coordinated network to standardise procedures. Treatment is free for all patients: standard regimens for drug-susceptible TB and individualised regimens for RR/MDR-TB, based on DST. Specialists manage treatment, and expert consultation is advised for complex cases. While second-line drugs are accessible, some difficulties in authorising newer agents such as bedaquiline and delamanid have been noted. None of the patients in our cohort was treated with the BPaLM regimen (bedaquiline, pretomanid, linezolid and moxifloxacin), as it was introduced later during the study period.
The aim of this study was to analyse the characteristics of rifampicin-resistant tuberculosis patients in Spain and their treatment and clinical outcomes.
Materials and methods
Study design and patients
This was an ambispective observational study of a multicentre cohort of rifampicin-resistant tuberculosis patients, including RR-TB, MDR-TB, pre-XDR-TB and XDR-TB. Patients were recruited between January 2019 and June 2023 across 38 centres in Spain. Those diagnosed between 2019 and 2020 were retrospectively included, whereas cases from 2021 onwards were prospectively recruited. The study was conducted by members of the Tuberculosis and Nontuberculous Mycobacteria Research Programme (PII-TB&MNT) of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). This research network includes pulmonologists, internal medicine and infectious diseases specialists, microbiologists, epidemiologists, case management nurses and Clinical Tuberculosis Units accredited by SEPAR [12]. The recruitment of patients was consecutive. Patients were followed up through regular visits and clinical assessments according to the standardised protocol of each participating centre. Data on treatment progress, adherence and clinical outcomes were systematically recorded. The attending physician ensured consistent follow-up of the patient during the treatment period. Multicentre coordination ensured consistency in follow-up procedures.
The sample size corresponds to the number of cases collected over several years. Given the lack of precise data on the annual incidence of rifampicin-resistant tuberculosis cases in Spain, it was difficult to perform a formal sample size calculation. Therefore, the study includes all eligible patients diagnosed within the study period to maximise representativeness.
Patient data were recorded in the anonymised PII-TB&MNT database, which each researcher accessed with a personal identifier and password from 2021 onwards. A specific survey was designed to collect data on risk factors for rifampicin-resistant tuberculosis (previous tuberculosis diagnosis and treatment, place of origin and birth, and contact with drug-resistant tuberculosis patients), diagnostic methods used to detect Mycobacterium tuberculosis resistance (by phenotypic and/or molecular tests performed at each hospital using locally available equipment and techniques), drugs to which resistance was detected, and the individualised treatment regimen prescribed by the attending physician (drugs, regimens, dosages, treatment duration and side effects).
Additional data included administrative difficulties in obtaining drug authorisation and prescriptions, consultation or supervision of the initial treatment regimen by expert tuberculosis specialists or accredited Clinical Tuberculosis Units, and whether patients experienced difficulties understanding their treatment.
The inclusion of cases followed the ethical requirements outlined in the Declaration of Helsinki (October 2013 revision, Fortaleza, Brazil) and Spain's Organic Law on Data Protection 15/1999. The study was approved by the Research Ethics Committee of the Principality of Asturias.
Inclusion criteria
Microbiological diagnosis of tuberculosis (molecular tests and/or smear microscopy and/or positive culture).
Rifampicin resistance alone (RR-TB) or in combination with other drugs (MDR/pre-XDR/XDR-TB) confirmed by molecular and/or phenotypic tests.
Patient signed informed consent if recruited prospectively.
Exclusion criteria
Patients diagnosed with drug-susceptible tuberculosis, or those with resistance only to isoniazid or other drugs except rifampicin.
Definitions
Treatment outcomes definitions: cured, treatment completed, treatment failure, death due to tuberculosis or another cause, not evaluated or loss to follow-up (table 1). Definitions and criteria established by the WHO in 2013 [13], incorporated into SEPAR's 2017 tuberculosis treatment guidelines (updated in 2020) [14, 15], and modified WHO criteria published in 2021 [2] were used.
Successful treatment: defined as the sum of cured and treatment completed cases.
Difficulties in understanding treatment: problems in patient comprehension due to language, cultural or social barriers.
An expert in tuberculosis is a clinician with substantial experience in treating or advising on the management of tuberculosis patients, acknowledged for their contributions to clinical practice, research or guidelines at a broader professional level.
TABLE 1.
Treatment outcomes definitions
| Cured | Completed treatment as recommended by national policy with no evidence of failure and at least three consecutive negative cultures taken at least 30 days apart after the intensive phase. |
| Treatment completed | Completed treatment as recommended by national policy with no evidence of failure, but without documentation of at least three consecutive negative cultures taken at least 30 days apart after the intensive phase. |
| Treatment failure | Treatment discontinued or requires a permanent regimen change, including at least two anti-TB drugs, due to: lack of conversion “at the end of the intensive phase” or bacteriological reversion “in the continuation phase after conversion” to negative, or evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs or adverse drug reactions. |
| Death | A TB patient who dies for any reason before starting or during the course of treatment. |
| Lost to follow-up | A TB patient who did not start treatment or interrupted treatment for 30 consecutive days. |
| Not evaluated | A TB patient for whom a treatment outcome has not been assigned. This includes cases “transferred” to another treatment unit and cases where the treatment outcome is unknown. |
Statistical analysis
A descriptive analysis of the sample variables was performed. For comparisons of continuous variables, a t-test or Mann–Whitney U-test was used if the variable did not follow a normal distribution. For categorical variables, the chi-squared test was applied. A stepwise forward logistic regression model was designed, using successful treatment as the dependent variable. A p-value <0.05 was considered statistically significant. The IBM SPSS Statistics 25 software package was used for data analysis. Regarding missing data, if information from a specific patient was incomplete or unavailable, that case was excluded from the particular analysis involving the missing data. This approach was justified by the minimal proportion of missing data and the assumption that the data were missing at random, thus minimising potential bias.
Results
General characteristics
Of the 95 patients initially considered for inclusion, one was excluded due to refusal to sign the informed consent form, resulting in a final cohort of 94 patients with a mean age of 38.0±17.8 years; 67 were male (71.3%) and 27 female (28.7%). They were born in 24 different countries: 32 (33%) were from Spain and 63 (67%) from other countries (foreign-born) (Peru 14, Ukraine 7, Russia 6, Morocco 4 and 33 cases from 19 other countries). Additionally, 6 (6.4%) were HIV-infected. Previous tuberculosis treatment had been received by 24 patients (25.5%). The patients came from 13 out of the 17 Spanish Autonomous Communities as well as from the Autonomous City of Ceuta (Catalonia 27 cases, Andalusia 16, Madrid 15, the Basque Country 9, Canary Islands 8, Valencia 7, Asturias 3, Castilla-La Mancha 2, Galicia 2, Aragon 1, Cantabria 1, Ceuta 1, Murcia 1 and Navarre 1). The general characteristics are summarised in table 2.
TABLE 2.
Patient characteristics
| Total | N=94 |
|---|---|
| Sex | |
| Male | 67 (71.3) |
| Female | 27 (28.7) |
| Age, years | 38.0±17.8 |
| Country of birth | |
| Spain | 31 (32.9) |
| Others# | 63 (67.1) |
| Smoking habit | |
| Smoker | 40 (42.6) |
| Nonsmoker | 47 (50.0) |
| Former smoker | 7 (7.4) |
| Alcohol consumption | |
| Yes | 25 (26.6) |
| Drugs use | |
| Yes | 13 (13.8) |
| HIV infection | |
| Yes | 6 (6.4) |
| Other immunosuppression | |
| Yes | 7 (7.4) |
| Previous tuberculosis diagnosis | |
| Yes | 24 (25.5) |
| Correct treatment | |
| No | 11 (11.7) |
| Yes | 8 (8.5) |
| Previous contact with tuberculosis. | |
| Yes | 24 (25.5) |
| With drug-resistant tuberculosis | 10 (10.6) |
| Living situation | |
| Family | 53 (56.4) |
| Group | 17 (18.1) |
| Alone | 13 (13.8) |
| Homeless | 8 (8.5) |
| Confinement | 3 (3.2) |
| Inclusion of patients by year | 2019 (22), 2020 (22), 2021 (25), 2022 (16), 2023 (up to June) (9) |
Data are presented as n (%) or mean±sd. #: Interval from arrival in Spain to diagnosis of tuberculosis in 47 cases: 0–6 months in 12 (25.5%); 6 months to 1 year in 7 (14.9%); 1–5 years in 14 (29.8%); and more than 5 years in 14 cases (29.8%).
Clinical characteristics and diagnostic methods
Pulmonary involvement was the most common, in 83 cases (88.3%). The pulmonary radiological presentation was cavitary in 45 cases (47.9%) and bilateral in 36 (38.3%). Smear microscopy was positive in 55 patients (58.5%). To diagnose M. tuberculosis resistance, both molecular and phenotypic tests were used in 58 patients (61.7%) (results were concordant in 39 cases, discordant in 6 and in 13 cases, information on concordance or discordance was not recorded); only molecular techniques were used in 23 (24.5%) and only phenotypic tests in 10 (10.6%), with data missing for 3 cases; in total, molecular tests were used in 81 patients (86.2%) and phenotypic studies in 68 (72.3%). The most analysed sample was sputum, in 64 patients (68.1%), followed by bronchoscopy samples in 25 (26.6%). The clinical characteristics and diagnostic methods are summarised in table 3.
TABLE 3.
Clinical features and diagnostic methods
| Total | N=94 |
|---|---|
| Disease location | |
| Pulmonary | 83 (88.3) |
| Pleural | 9 (9.6) |
| Disseminated | 8 (8.5) |
| Extrapulmonary | 7 (7.4) |
| Symptoms | |
| Any symptom | 83 (88.3) |
| Cough | 66 (70.2) |
| Expectoration | 44 (46.8) |
| Fever | 34 (36.2) |
| Haemoptysis | 17 (18.1) |
| Weight loss | 38 (40.4) |
| Chest radiography | |
| Normal | 9 (9.6) |
| Cavitary | 45 (47.9) |
| Noncavitary | 40 (42.6) |
| Bilateral | 36 (38.3) |
| Unilateral | 30 (31.9) |
| Smear microscopy | |
| Positive | 55 (58.5) |
| Negative | 38 (40.4) |
| Not done | 1 (1.1) |
| Diagnostic specimens | |
| Sputum | 64 (68.1) |
| Bronchial aspirate, BAL | 25 (26.6) |
| Exudates | 4 (4.3) |
| Histology, tissue biopsy | 9 (9.5) |
| Gastric aspirate | 8 (8.5) |
| Others | 6 (6.4) |
| Diagnostic tests for resistance # | |
| Phenotypic and molecular tests¶ (4 discordant) | 58 (61.7) |
| Phenotypic tests only | 10 (10.6) |
| Molecular tests only | 23 (24.5) |
| Molecular tests positive | 77 (81.9) |
| Histology (biopsies) | 9 (9.5), 7 positives |
| Place of microbiological diagnosis | |
| Own hospital | 35 (37.2) |
| Reference hospital | 35 (37.2) |
| Both in collaboration | 23 (24.5) |
Data are presented as n (%). BAL: bronchoalveolar lavage; MDR-TB: multidrug-resistant; XDR: extensively drug-resistant. #: We found resistance to rifampicin in 94 cases, isoniazid (n=82), pyrazinamide (n=35), ethambutol (n=26), aminoglycosides (n=19) and fluoroquinolones (n=10). ¶: Molecular techniques, data in 69 patients: GeneXpert (n=36), GenoType MTBDRplus (n=32) only or in combination, Anyplex II MTB/MDR/XDR Detection (n=9) and whole-genome sequencing (n=1).
Classification and treatment
According to the current WHO definitions on drug resistance, 9 patients had RR-TB, 75 had MDR-TB, 9 had pre-XDR-TB and 1 had XDR-TB.
Regarding the number of drugs used, the mean was 4.9±1.2 and the median was 5 (range 3–8). Linezolid was administered to 87 patients (92.6%), fluoroquinolones to 82 (87.2%), bedaquiline to 39 (41.5%), clofazimine to 64 (68%), cycloserine to 42 (44.6%), amikacin to 25 (26.5%), 20 of whom did not receive concurrent bedaquiline, and delamanid to 27 (28.7%). The mean treatment duration was 11.2±4.9 months. The attending physician sought treatment regimen advice to experts in 63 patients (67%). Difficulties in obtaining authorisation and prescribing of medications were reported in 43 patients (45.7%): 30 (31.9%) with bedaquiline and 13 (13.8%) with delamanid; these issues were primarily due to administrative barriers and the requirement for prior approval for these high-cost drugs within the Spanish healthcare system. Additionally, 21 patients (22.3%) experienced difficulties understanding the treatment; these difficulties were, not solely due to language barriers, which affected 14 patients (14.9%), but also related to low educational levels in 6 (6.4%), socioeconomic problems in 4 (4.2%) or poor treatment compliance in 3 (3.1%).
Side effects of medication were frequent among patients in our cohort. The most commonly observed included neurological symptoms in 20 (21.3%), haematological alterations in 18 (19.1%), hepatic/analytic changes in 18 (19.1%) and electrocardiographic changes in 4 (4.3%), mainly QT interval prolongation. In several cases, adverse events led to treatment discontinuation of specific drugs, including linezolid (n=5), fluoroquinolones (n=2), aminoglycosides (n=2), high-dose isoniazid (n=1) and protionamide (n=1).
The treatment was successful in 83 patients (88.3%) (60 cured and 23 with completed treatment), whereas it was unsuccessful in the remaining cases: 3 deaths (3.5%), 2 of which were due to TB, 5 patients lost to follow-up (5.3%) and 3 not evaluated (3.5%). There were no treatment failures as final classification, although we identified three patients who initially experienced poor clinical evolution, requiring modifications to their treatment regimen. All three were ultimately classified as treatment successes (one cured and two with completed treatment).The characteristics and type of treatment are summarised in table 4.
TABLE 4.
Characteristics and type of treatment
| Total | N=94 |
|---|---|
| Right to public healthcare # | |
| Yes | 76 (80.9) |
| Supervised treatment regimen | |
| Yes | 63 (67) |
| Per expert individual | 38 (40.4) |
| Expert group | 12 (12.8) |
| Scientific societies | 5 (5.3) |
| Autonomous Communities committees | 3 (3.2) |
| Difficulties in drug authorisation | |
| Yes | 43 (45.7) (30 bedaquiline, 13 delamanid) |
| Treatment comprehension difficulties | |
| Yes | 21 (22.3) |
| Treatment, number of drugs | 4.9±1.2, 5 (3–8). |
| Use of drugs | |
| Bedaquiline | 39 (41.5) |
| Linezolid | 87 (92.6) |
| Fluoroquinolones | 82 (87.2) |
| Clofazimine | 64 (68) |
| Cycloserine | 42 (44.6) |
| Amikacin | 25 (26.5) |
| Delamanid | 27 (28.7) |
| Treatment duration, months | 11.2±4.9 (1–24) |
| Culture conversion time, months | 4±7.6 (1–24) |
| Side effects of medication | |
| Analytic alterations, mainly hepatic | 18 (19.1) |
| Haematological | 18 (19.1) |
| Neurological | 20 (21.3) |
| ECG alterations (QT interval prolongation) | 4 (4.3) |
| Others | 22 (23.4) |
| Discontinuation of drugs¶ | 11 (11.7) |
| Final classification of treatment | |
| Cured | 60 (63.8) |
| Treatment completed | 23 (24.5) |
| Loss of follow-up | 5 (5.3) |
| Not assessed | 3 (3.2) |
| Death | 3 (3.2), 2 of them by tuberculosis. |
| Treatment failure | 0 |
| Successful treatment | 83 (88.3) |
| Unsuccessful treatment | 11 (11.7) |
Data are presented as mean±sd, n (%) or median (range). #: All patients received free healthcare and treatment under the public health system without any discrimination for undocumented. ¶: Discontinuation of drugs: linezolid (n=5), fluoroquinolones (n=2), aminoglycosides (n=2), high-dose isoniazid (n=1) and protionamide (n=1).
In univariate analysis, successful treatment was significantly associated with MDR-TB diagnosis (94.6% success in MDR-TB versus 60.0% in the combined group of pre-XDR-TB, six out of nine patients, and XDR, none out of one patient), with fluoroquinolone use (90.2% success versus 66.7% without fluoroquinolones), and with the absence of difficulties in understanding the treatment (95.8% success versus 61.9% when patients had understanding difficulties). However, in multivariate analysis, only the tuberculosis resistance profile and treatment comprehension maintained independent associations. Patients diagnosed with MDR-TB were significantly more likely to achieve successful outcomes compared with those with pre-XDR-TB/XDR-TB (OR 8.77, 95% CI 1.42–45.55; p=0.01). Similarly, patients without treatment comprehension difficulties were more likely to achieve successful treatment (OR 10.61, 95% CI 2.78–40.48; p=0.001) (table 5). To avoid excluding the single XDR-TB case and ensure consistency across analyses, pre-XDR and XDR cases were grouped together. A sensitivity analysis including only the pre-XDR subgroup yielded similar results.
TABLE 5.
Univariate and multivariate analysis in relation to treatment success
| Variables | Successful treatment | Univariate OR, CI 95% |
p-value | Multivariate OR, CI 95% |
p-value |
|---|---|---|---|---|---|
| Sex | |||||
| Male | 57 (85.1) | 1 | 0.12 | ||
| Female | 26 (96.3) | 0.88, 0.78–1.00 | |||
| Origin | |||||
| Native | 28 (90.3) | 1.03, 0.89–1.20 | 0.66 | ||
| Foreign-born | 55 (87.3) | 1 | |||
| HIV | |||||
| Positive | 6 (100) | 0.87, 0.81–0.95 | 0.94 | ||
| Negative | 77 (87.5) | 1 | |||
| Type | |||||
| RR-TB | 6 (66.7) | 1.20, 0.16–8.79 | 0.01 | 1.37, 0.12–15.13 | 0.79 |
| MDR-TB | 71 (94.6) | 12, 2.38–40.93 | 8.77, 1.42–45.55 | 0.01 | |
| Pre-XDR-TB, XDR-TB | 6 (60.0) | 1 | 1 | ||
| Supervised treatment | |||||
| Yes | 56 (88.9) | 1.18, 0.23–2.13 | 0.81 | ||
| No | 27 (87.1) | 1 | |||
| Difficulties in comprehension | |||||
| Yes | 13 (61.9) | 1 | 1 | ||
| No | 70 (95.8) | 9.27, 2.69–21.87 | 0.001 | 10.61, 2.78–40.48 | 0.001 |
| Right to healthcare | |||||
| Yes | 66 (86.8) | 2.57, 0.95–5.40 | 0.52 | ||
| No | 17 (94.1) | 1 | |||
| Difficulties in authorisation | |||||
| Yes | 39 (90.7) | 2.10, 0.98–5.32 | 0.44 | ||
| No | 44 (86.3) | 1 | |||
| Treatment | |||||
| Bedaquiline | |||||
| Yes | 36 (92.3) | 1.08, 0.93–1,24 | 0.30 | ||
| No | 47 (85.4) | 1 | |||
| Linezolid | |||||
| Yes | 77 (88.5) | 1.28, 0.14–11.78 | 0.82 | ||
| No | 6 (85.7) | 1 | |||
| Fluoroquinolones | |||||
| Yes | 74 (90.2) | 4.62, 1.13–18.84 | 0.02 | 1.49, 0.11–19.23 | 0.75 |
| No | 8 (66.7) | 1 | 1 | ||
| Delamanid | |||||
| Yes | 25 (92.5) | 1.94, 0.39–9.63 | 0.41 | ||
| No | 58 (86.6) | 1 | |||
| Previous TB | |||||
| Yes | 23 (95.8) | 3.04, 0.45–20.39 | 0.18 | ||
| No | 60 (85.7) | 1 | |||
| Location | |||||
| Pulmonary | 73 (88.0) | 1 | 0.77 | ||
| Extrapulmonary | 10 (90.9) | 0.73, 0.08–6.32 | |||
Data are presented as mean±sd or n (%). OR: odds ratio; TB: tuberculosis; RR-TB: rifampicin-resistant tuberculosis; MDR-TB: multidrug-resistant tuberculosis; XDR-TB: extensively drug-resistant tuberculosis.
Subgroup comparisons
Retrospective versus prospective cases
We compared baseline and treatment-related variables between patients recruited during the retrospective (2019–2020) and prospective (2021–2023) periods. No significant differences were found in age, sex or proportion of foreign-born patients. The retrospective group received a significantly higher number of drugs and had longer treatment duration. The use of bedaquiline, linezolid and fluoroquinolones increased in the prospective cohort, though differences were not statistically significant. In contrast, amikacin was used significantly more often in the retrospective group. Treatment success rates were similar in both periods (table 6).
TABLE 6.
Differences between patients with retrospective and prospective recruitment
| Variable | 2019–2020 (n=44) | 2021–2023 (n=50) | p-value |
|---|---|---|---|
| Age, years | 37.4±19.7 | 38.5±16.0 | 0.76 |
| Sex | 0.45 | ||
| Male | 33 (75.0) | 34 (68.0) | |
| Female | 11 (25.0) | 16 (32.0) | |
| Origin | 0.51 | ||
| Spanish | 16 (36.4) | 15 (30.0) | |
| Foreign-born | 28 (63.6) | 35 (70.0) | |
| Number of drugs | 5.2±1.2 | 4.6±1.1 | 0.02 |
| Treatment duration, months | 12.9±4.7 | 9.7±4.3 | 0.001 |
| Successful treatment outcome | 38 (86.4) | 45 (90.0) | 0.58 |
| Bedaquiline treatment | 14 (31.8) | 25 (50.0) | 0.07 |
| Fluoroquinolone treatment | 36 (81.8) | 46 (92.0) | 0.14 |
| Linezolid treatment | 39 (88.6) | 48 (96.0) | 0.17 |
| Amikacin treatment | 16 (36.4) | 9 (18.0) | 0.04 |
Data are presented as mean±sd or n (%).
Patients with versus without bedaquiline treatment
Patients treated with bedaquiline had significantly shorter treatment durations, received fewer drugs and were less frequently treated with concomitant amikacin compared with those not treated with bedaquiline. No significant differences were observed in treatment success between the groups (table 7).
TABLE 7.
Differences between patients treated with or without bedaquiline
| Variable | Bedaquiline, yes (n=39) | Bedaquiline, no (n=55) | p-value |
|---|---|---|---|
| Number of drugs | 4.4±1.3 | 5.2±1.0 | 0.04 |
| Treatment duration, months | 10.2±4.9 | 11.9±4.6 | 0.09 |
| Concomitant treatment with amikacin | 5 (12.8) | 20 (36.3) | 0.02 |
| Successful treatment outcome | 38 (90.7) | 44 (86.3) | 0.44 |
Data are presented as mean±sd or n (%).
Pulmonary versus extrapulmonary tuberculosis
Treatment duration and outcomes did not differ significantly. Patients with extrapulmonary TB tended to receive more drugs than those with pulmonary TB (5.5±1.5 versus 4.8±1.1; p=0.08) (table 8).
TABLE 8.
Differences between pulmonary and extrapulmonary tuberculosis
| Variable | Pulmonary (n=83) | Extrapulmonary (n=11) | p-value |
|---|---|---|---|
| Number of drugs | 4.8±1.1 | 5.5±1.5 | 0.08 |
| Treatment duration, months | 11.3±5.0 | 10.5±2.0 | 0.60 |
| Successful treatment outcome | 73 (88.0) | 10 (90.9) | 0.77 |
Data are presented as mean±sd or n (%).
Discussion
Our cohort study on rifampicin-resistant tuberculosis patients treated in Spain, from most Autonomous Communities, demonstrates a high percentage of patients from countries other than Spain, difficulties in drug authorisation and prescription of bedaquiline and delamanid, and good adherence among patients, translating into a high treatment success rate.
The proportion of foreign-born patients in our cohort is high (67%) and significantly exceeds the proportion reported in drug-susceptible tuberculosis: 40.3% in a study conducted by the PII-TB&MNT on 1769 patients registered between 2017 and 2020 [16], and 34.3% in the 2023 RENAVE report on tuberculosis in Spain. According to the ECDC, the corresponding figures were 40.7% in Spain and 33.3% in the European Union for drug-susceptible tuberculosis [9, 11]. This may reflect the arrival of patients from countries where tuberculosis incidence, particularly RR/MDR-TB, is higher than in Spain. However, molecular epidemiological data to determine whether tuberculosis was imported or locally acquired were not available for our cohort. A similarly high proportion of foreign-born MDR-TB patients has also been observed in other series, such as a recent Finnish study in which 70.2% of MDR-TB patients came from other countries [17]. Our findings are also consistent with a recent meta-analysis on tuberculosis in recent migrants to Europe, which reported an increased risk of RR/MDR-TB among migrants compared with the nonmigrant population (OR 3.16, 95% CI 1.69–5.92) [18], highlighting the need to reduce the burden of tuberculosis among migrants in low-incidence countries [19].
Regarding prior tuberculosis treatment, 24 patients (25.5%) had received previous treatment that is a known risk factor for developing rifampicin-resistant tuberculosis, as confirmed by the latest WHO report [6], which states that 3.2% of new cases had RR/MDR-TB, while this percentage rose to 16% in previously treated cases. In Russia and certain Eastern European and Central Asian countries, this percentage exceeds 50%.
Concerning the treatment administered (individually tailored for each patient according to national and international guidelines [4, 5, 14, 15]) a high proportion of patients received linezolid and fluoroquinolones (92.6% and 87.2%, respectively), in contrast to the fact that fewer than half received bedaquiline (41.5%). This limited use of bedaquiline usage contrasts with national and international guidelines, which prioritise its use alongside the other WHO Group A drugs [15, 20–22]. The low proportion of patients receiving bedaquiline (and also delamanid) can be attributed to the difficulties in obtaining authorisation and prescriptions from the health system, as reported in 45.7% of cases. It is desirable that bedaquiline usage increases significantly in the future, in line with national and international recommendations and following the recent decision by Spain's Ministry of Health to include bedaquiline among publicly funded medications [23]. A recent study in the WHO European region highlights a widespread lack of access to essential antituberculosis medications, including bedaquiline and delamanid, in several countries, along with the high costs associated with treating drug-resistant tuberculosis [24]. These barriers, including administrative restrictions and high drug prices, represent a significant challenge to effective management and align with our findings within the Spanish healthcare context. Addressing these issues is critical to improving treatment access and outcomes for patients. Despite the limited use of bedaquiline, the overall high treatment success rate (88.3%) may be explained by the expert-guided individualised regimens applied in most cases, the widespread use of other key second-line drugs such as linezolid, fluoroquinolones and clofazimine and the low proportion of patients with pre-XDR-TB or XDR-TB in our cohort.
We observed that patients recruited in the later period of our study received fewer drugs and had shorter treatment durations. This likely reflects evolving clinical practice and the increased use of newer drugs such as bedaquiline and linezolid. The reduced use of amikacin also suggests that it becomes less necessary when these newer agents are available. These changes indicate a trend toward more optimised treatment regimens in recent years.
In relation to treatment guidance, advice on regimen selection was sought from Clinical Tuberculosis Units or expert clinicians in 67% of cases. Given the low number of drug-resistant tuberculosis patients in Spain relative to the number of physicians treating them, gaining clinical experience in managing these cases is challenging. This underscores the importance of consulting expert guidance, as recommended in SEPAR's rifampicin-resistant tuberculosis guidelines [14, 15]. The high proportion of cases in which treatment advice was sought is therefore considered a positive and noteworthy finding.
With respect to final patient classification, the results indicate a high treatment success rate (88.3%), which can be considered highly satisfactory. Treatment success rates for RR/MDR-TB vary widely across studies, depending on factors such as national incidence, healthcare resources and the type of treatment regimen (individualised versus standardised). A recent study collecting data from 16 low-incidence European countries [25] reported treatment success rates ranging from 72% to 85%.
Regarding treatment outcomes, success rates differed between groups under the new WHO classification, being higher in MDR-TB (success 71 of 74, 94.6%) compared with pre-XDR-TB (success 6 of 9, 66.7%), This finding underscores the negative impact of fluoroquinolone resistance on treatment outcomes, consistent with previous studies [26–28] and highlights the need for further research into strategies to improve treatment success in individuals with fluoroquinolone resistance [29].
Moreover, we found that patients with limited treatment comprehension (due to language barriers, cultural factors or socioeconomic challenges) had lower treatment success rates. This finding is consistent with previous observations by our research group, which linked these factors to increased treatment non-adherence and mortality [30, 31]. These results underscore the importance of patient education and support to enhance comprehension and, consequently, treatment adherence and success, as well as the involvement of multidisciplinary teams, including community advisors and cultural mediators in tuberculosis control [32].
Adverse events related to treatment were frequent in our cohort and represent one of the main challenges in managing drug-resistant tuberculosis. While most adverse events were manageable, treatment discontinuation of key drugs such as linezolid, fluoroquinolones and aminoglycosides was required in several cases. These findings highlight the importance of continuous clinical and laboratory monitoring, as well as the need for broader and more agile access to new therapeutic options with better safety profiles.
As a limitation, it cannot be guaranteed that the study includes all patients diagnosed and treated in Spain. However, the data have been provided by professionals from the PII-TB&MNT, covering the majority of Spanish hospitals and Clinical Tuberculosis Units responsible for cases with treatment difficulties. Therefore, we believe they represent most of these cases, making the data presented in this study representative of the situation in Spain.
Additionally, as this study reflects routine clinical practice, with treatments individually tailored for each patient following national and international guidelines and, in most cases, expert advice, it is not possible to analyse which treatment regimens yield the best outcomes.
Post-treatment follow-up data were not available, as long-term outcomes, such as sustained treatment success according to WHO definitions, were not part of the study objectives.
As a strength, we rely on the research experience of members of SEPAR's multidisciplinary Tuberculosis working group (PII-TB&MNT) [33] and the significant effort made to include the largest possible number of cases through information from reference laboratories for tuberculosis diagnosis and continuous contact with the network of researchers from most Spanish hospitals and Autonomous Communities.
In conclusion, among patients with rifampicin-resistant tuberculosis in Spain (with a high proportion being foreign-born) treatment success was high, achieved through individualised regimens based on national and international recommendations, and supported by expert guidance in a large proportion of cases, despite limitations in the use of bedaquiline due to authorisation issues. Patients with pre-XDR-TB had significantly poorer outcomes compared with those with MDR-TB, highlighting the greater clinical challenge posed by pre-XDR-TB cases. Moreover, the critical role of treatment comprehension in achieving positive outcomes underscores the need for comprehensive patient education and tailored support interventions to enhance treatment success rates in rifampicin-resistant tuberculosis.
Acknowledgements
Thanks to all the people who, although not mentioned, have collaborated with the Working Group on Rifampicin-Resistant Tuberculosis in this study. During the preparation of this work the authors used ChatGPT to initiate translation from Spanish to English. After using this tool, J-M. García-García, J-A. Gullón-Blanco and E. Tabernero Huguet, with the supervision of Robert D. Bachum (native English teacher), reviewed and edited the content as needed and take full responsibility for the content of the publication.
Footnotes
Provenance: Submitted article, peer reviewed.
Working Group on Rifampicin Resistant Tuberculosis of the Tuberculosis Research Programme (PII-TB), SEPAR: Elena Martínez Robles (Hospital Universitario La Paz-Cantoblanco-Carlos III, Madrid, Spain), Julen Cadiñanos Loidi (Hospital Universitario La Paz, Madrid, Spain), María Castillo García (Hospital Universitario de Guadalajara, Guadalajara, Spain), José Luis Izquierdo Alonso (Hospital Universitario de Guadalajara, Guadalajara, Spain), Luis Borderías Clau (Hospital General Universitario San Jorge de Huesca, Huesca, Spain), Mariara Calderón Alcalá (Hospital Universitario Infanta Leonor, Madrid, Spain), Isabel Carpena Martínez (Hospital General Universitario José M Morales Meseguer, Murcia, Spain), María Elisa Cordero Matía (Hospital Universitario Virgen del Rocío, Seville, Spain), Salvador De la Torre Carazo (Hospital Central de la Defensa Gómez Ulla, Madrid, Spain), Pablo Fernández Álvarez (Hospital Universitario San Agustín, Avilés, Asturias, Spain), Fernando Álvarez Navascués (Hospital Universitario San Agustín, Avilés, Asturias, Spain), Begoña Fernández Infante (Complejo Hospitalario de Navarra, Pamplona, Spain), Lucía Ferreiro Fernández (Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain), Sara Hernández Egido (Hospital Universitario Severo Ochoa, Leganés, Spain), Belén Navas Bueno (Hospital General Básico Santa Ana de Motril, Motril, Spain), Antoni Noguera Julián (Hospital Sant Joan de Déu, Barcelona, Spain), Oscar Ozoleto Camacho (Hospital Universitario de Ceuta, Ceuta, Spain), Guillermo Pérez Mendoza (Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain), Jesús Rodríguez González (Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain), Agustín Ruiz González (Hospital Universitario Arnau de Vilanova, Lleida, Spain), Asunción Seminario Ruiz (Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain), Paz Valiño López (Complejo Hospitalario Universitario Juan Canalejo, La Coruña, Spain), Miguel Zabaleta Murguiondo† (Hospital Universitario Marqués de Valdecilla, Santander, Spain), Patricia Mínguez Clemente (Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain), Antonio Castanera Moros (Hospital Royo Villanova, Zaragoza, Spain) and Sandra Pérez Recio (Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Spain).
Ethics statement: The study was approved by the Research Ethics Committee of the Principality of Asturias. Maximum confidentiality is recommended with the study data.
Author contributions: J-M. García-García: conception and design of the study; acquisition, analysis and interpretation of data; and writing of the article. T. Rodrigo-Sanz, J-A. Gullón-Blanco and J.A. Caminero Luna: review of the intellectual content and final approval of the version presented. J-A. Gullón-Blanco: methodology design and statistical analysis of data. J-J. Palacios Gutiérrez, Fernando Alcaide and S. Samper Blasco: microbiological technical assistance. E. Tabernero Huguet, J.A. Caylà and J. Ruiz Manzano: revision and final approval of the version presented. Rest of authors and members of PII-TB: collection and contribution of data.
Conflict of interest: None declared.
Support statement: This study was supported by Sociedad Española de Neumología y Cirugía Torácica grant 1100/2020. Funding information for this article has been deposited with the Open Funder Registry.
Contributor Information
the Working Group on Rifampicin Resistant Tuberculosis of the Tuberculosis Research Programme (PII-TB) SEPAR:
Elena Martínez Robles, María Castillo García, José Luis Izquierdo Alonso, Luis Borderías Clau, Mariara Calderón Alcalá, Isabel Carpena Martínez, María Elisa Cordero Matía, Salvador De la Torre Carazo, Pablo Fernández Álvarez, Fernando Álvarez Navascués, Begoña Fernández Infante, Lucía Ferreiro Fernández, Sara Hernández Egido, Belén Navas Bueno, Antoni Noguera Julián, Oscar Ozoleto Camacho, Guillermo Pérez Mendoza, Jesús Rodríguez González, Agustín Ruiz González, Asunción Seminario Ruiz, Paz Valiño López, Miguel Zabaleta Murguiondo, Patricia Mínguez Clemente, Antonio Castanera Moros, and Sandra Pérez Recio
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