Use of linezolid and bedaquiline in patients with pulmonary tuberculosis in the postoperative period

Introduction 

The epidemic situation for tuberculosis (TB) in the Russian Federation in 2023 remains stable compared to 2022. The incidence rate of TB, as in 2022, remained at 31.1 per 100 thousand population, the mortality rate from TB in 2023 was 3.8 per 100 thousand population. Yet, the spread of multidrug-resistant TB (MDR-TB) in Russia (defined as resistance of Mycobacterium tuberculosis [MTB] to both isoniazid and rifampicin, regardless of resistance to other anti-tuberculosis drugs [ATDs] and extensively drug-resistant TB (XDR-TB), characterized by resistance of MTB to rifampicin with or without resistance to isoniazid in combination with resistance to any fluoroquinolone, still persists [1, 2]. 

The emergence of MTB strains resistant to the most effective drugs is among the major problems preventing the reduction of TB spread [3]. The use of new ATDs plays an important role in increasing the effectiveness of treatment for people with MDR-TB and XDR-TB. The introduction of new ATDs into MDR-TB and XDR-TB treatment regimens involves, among other things, the use of drugs aimed at treating other infections [4, 5].

The possible tuberculostatic properties of linezolid (Lzd) were expected since its introduction into medical practice. This was later confirmed by the effectiveness of combination regimens containing this drug [6]. In 2013, bedaquiline (Bq) was registered in Russia under the trade name of Sirturo (OAO Pharmstandard-UfaVITA, Russia, LP-002281). This medication is included in the List of Vital and Essential Medicines, as well as in the Clinical Guidelines for the Treatment of Tuberculosis in Adults, compiled by the Russian Society of Phthisiologists and approved by the Scientific and Practical Council of the Russian Federation Ministry of Healthcare as a drug for the treatment of MDR-TB and XDR-TB [2, 7]. However, some previous studies of MTB isolates with MDR and XDR reported the emergence of resistance to Lzd and Bq with a frequency ranging 1.0–10.8% [8–11]. 

The leading role in the effectiveness of treating the patients with MDR-TB and XDR-TB belongs to the fastest possible detection of its drug sensitivity to ATDs. Resected areas of the lungs are more informative for subsequent correction of therapy, thereby providing a personalized approach to treatment [12]. 

In the postoperative period, it is crucial to come up with a chemotherapy regimen, taking into account the results of examining the most informative biological material, and to investigate the effectiveness and safety of including new ATDs in combination therapy.

Objective: to assess the effectiveness of MDR-TB and XDR-TB chemotherapy regimens with the inclusion of Lzd and Bq in patients who underwent a surgery for pulmonary TB.

Materials and Methods

To assess the effectiveness of chemotherapy in the postoperative period and the tolerability of new ATDs, we conducted a nonrandomized continuous single-center retrospective clinical trial. 

The study included 154 patients with MDR-TB and XDR-TB diagnosed based on resection material. All patients were operated at the National Medical Research Center for Phthisiology and Infectious Diseases, Moscow, Russia. 

Inclusion criteria were as follows: 

•       Men and women over the age of 18 years; 

•       Performed lung resections of various extent depending on the clinical form of TB; 

•       MTB with MDR and XDR detected in resection material. 

Non-inclusion criterion for our study was HIV infection as a concomitant pathology.

The TB chemotherapy regimens in the patients included in the study were assigned based on the clinical recommendations relevant at the time of treatment, depending on the results of laboratory tests of resection material, the type of detected MTB drug resistance, the established clinical form of TB, the duration of previous therapy and the individual tolerability of ATDs. 

In all patients with MDR-TB/XDR-TB, the chemotherapy regimen included the prescribed second-line ATDs (levofloxacin, moxifloxacin, sparfloxacin, kanamycin, amikacin, capreomycin, cycloserine, terizidone, protionamide, ethionamide, aminosalicylic acid) and the first-line ATDs (pyrazinamide, ethambutol, streptomycin) while maintaining individual sensitivity to them.

In accordance with the study objective, two study groups of monitored patients were assigned: 

•       Group 1 consisted of patients with a chemotherapy regimen supplemented with new ATDs (Lzd and Bq); 

•       Group 2 included patients with MDR-TB/XDR-TB who received a traditional postoperative chemotherapy regimen that did not include Lzd and Bq.

The combinations and assortment of chemotherapy drugs in both study groups were determined individually for each patient by the medical examining board. A combination of 5-6 ATDs simultaneously was prescribed in the intensive phase of the chemotherapy regimen, while at least 3 ATDs were prescribed in the continuation phase.

Group 1, the treatment regimen was primarily based on Lzd (600 mg/day orally or intravenously) and Bq (400 mg once a day for the first 2 weeks, then 200 mg 3 times a week), with the addition of cycloserine or terizidone at a dose of 500-750 mg/day depending on body weight. The next most frequently prescribed drug was one of the fluoroquinolones, to which sensitivity remained; all things being equal, moxifloxacin was preferred. This was the most commonly used combination of ATDs: it was prescribed to 70 (80.5%) patients. To develop an effective chemotherapy regimen, we added 1-2 ATDs (to which MTB sensitivity was preserved) to the basic regimen. 

The characteristics of patients in the study groups based on the inclusion criteria are presented in Table 1.

Table 1. General characteristics of patients included in the study (n=154)

In the study groups, the patients were similar in both gender and age composition. Treatment was considered effective if the patient was transferred to the dispensary observation group 3 or removed from the TB dispensary register, while a persistent absence of MTB infection was observed, confirmed by the microbial seeding method, and the TB process was regarded as inactive based on clinical and radiological data (a favorable outcome). Treatment was considered ineffective (an unfavorable outcome) if the patient retained or resumed signs of an active TB process during the observation period [2]. The duration of patient follow-up in both groups ranged from 2 to 5 years. 

In Group 1, 96.5% (n=84/87) of patients were removed from the dispensary register or transferred to the dispensary observation group 3, 2 (2.3%) patients remained in the dispensary observation group 1. A recurrence of the TB process was noted in 1 (1.1%) patient two years after completion of the TB treatment course. 

In Group 2, 86.6% (n=58/67) of patients were removed from the dispensary register or transferred to the dispensary observation group 3, 3 (4.5%) patients were transferred to the dispensary observation group 2a. Recurrence of the disease during the 1st year after the completion of the chemotherapy course (after 8-11 months) was observed in 6 (9%) patients. The most common clinical form of TB in both groups were tuberculoma (including multiple tuberculoma): 73.9% of cases in Group 1 and 87.2% in Group 2 (Table 2).

Table 2. Clinical forms of tuberculosis and drug resistance in study groups

MBT, Mycobacterium tuberculosis; FCPT, fibrous cavernous pulmonary tuberculosis; CPT, cavernous pulmonary tuberculosis; MDR-TB, multidrug-resistant tuberculosis; XDR-TB, extensively drug-resistant tuberculosis.

In compliance with the 2022 clinical guidelines, Tuberculosis in Adults, we identified MDR-TB and XDR-TB [2]. In terms of the drug resistance spectrum, patients with MDR-TB prevailed in both Group 1 (n=67 or 77%) and Group 2 in (n=57 or 85%). 

Video-assisted thoracoscopic lung resection was performed in both study groups. E.g., double segmentectomy was the main type of surgical intervention: 57.5% (n=50/87) in Group 1 and 49.3% (n=33/67) in Group 2. The number and extent of performed surgical procedures are shown in Table 3. 

Table 3. Extent and nature of surgical interventions performed in two groups

FCPT, fibrous cavernous pulmonary tuberculosis; CPT, cavernous pulmonary tuberculosis.

A total of 154 surgeries were performed: 87 resections in Group 1 and 67 resections in Group 2.

The most common postoperative complication in both study groups was delayed lung expansion, in 5 (5.7%) patients of Group 1 and 9 (13.4%) patients of Group 2 (p=0.17). In addition, in the Study group 1, 1 patient with cavernous pulmonary tuberculosis (CPT) experienced pleural hemorrhage after lobectomy and 1 patient with fibrous cavernous pulmonary tuberculosis (FCPT) had bronchopleural fistula after pneumonectomy.

In Group 2, 3 patients with CPT experienced pleural hemorrhage after double segmentectomy and 2 with FCPT were diagnosed with bronchopleural fistula after pneumonectomy.

To assess the severity of adverse effects that developed during TB chemotherapy, we used the DMID (Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, USA) criteria and the toxicity criteria of the National Cancer Institute (USA) (Common Terminology Criteria for Adverse Events v. 5.0), which were developed for clinical trials involving antibiotics and antitumor drugs [13, 14]. 

Statistical data processing was carried out using the SPSS Statistics Base 27.0 software. The normality of the distribution was verified using the Kolmogorov–Smirnov test with the Lilliefors correction. A comparative analysis of categorical variables was performed using the χ2 criterion or the Fisher’s exact test; p<0.05 was considered statistically significant. When comparing qualitative features of related populations based on χ2 criterion, the McNemar test was employed, while for independent samples, we used multiple Kruskal-Wallis tests with Bonferroni correction. The differences were considered statistically significant at p<0.05.

Results

The duration of chemotherapy in the postoperative period prior to the onset of a favorable outcome was compared between two study groups (Table 4). The duration of ATD use complied with the decision of the medical examining board of the phthisiology service at the patient’s place of residence in accordance with the clinical guidelines for the treatment of TB.

As can be seen from Table 4, when Lzd and Bq were included in postoperative chemotherapy, the course duration was statistically significantly shorter by 6.1 weeks: 38.5 (SD: 2.1) weeks vs. 44.6 (SD: 2.2) weeks (p<0.05). 

Table 4. Duration of tuberculosis treatment in the postoperative period

m, mean; SD, standard deviation; CI, confidence interval.  

Proportions of adverse effects in both groups with ATDs prescribed without taking into account the use of Lsd and Bq were similar. Adverse effects were observed in 24.1% (n=21/87) in Group 1 vs. 25.4% (n=17/67) in Group 2. Table 5 shows the incidence of adverse effects of ongoing TB treatment.

Table 5. Proportions of adverse effects of tuberculosis treatment without taking into account the use of linezolid and bedaquiline

The development of adverse effects of the first-line and second-line ATDs in patients receiving therapy did not differ statistically significantly between the study groups.

However, the administration of Lzd and Bq was accompanied by the development of adverse effects specific to these drugs. For instance, when taking Lzd, myelosuppression was detected in 6.9% (n=6) of patients, while peripheral neuropathy was observed in 8% (n=7) of patients. The prescription of Bq in 9.2% (n=8) of patients was accompanied by an increase in the QT interval by more than 60 µs compared with the baseline value. A 30-60 µs increase in QT vs.  the baseline value was observed in 46.2% of patients in the group taking Bq, compared with 28.1% of patients in the control group, while not exceeding the physiological norm. The QT prolongation value was higher than the baseline value during the first 18 weeks of treatment, remained stable until week 24, and then gradually decreased. In 11.5% (n=10) of cases, patients in Group 1 experienced pain behind the sternum. The noted adverse effects were eliminable without reducing the dosage or discontinuing ATD. 

In Group 1, 85 (97.8%) patients were removed from the dispensary register or transferred to the dispensary observation group 3, 1 (1.1%) patient was still in the dispensary observation group 1. A recurrence of the TB process was noted in 1 patient (1.1%) two years after the completion of the TB treatment course. 

In Group 2, 62 (92.5%) patients were removed from the dispensary register or transferred to the dispensary observation group 3, 3 (4.5%) patients were transferred to the dispensary observation group 2a. Recurrence of the disease within a year after the chemotherapy course was detected in 2 (3%) patients (after 8 and 11 months).

Discussion

Despite numerous ATDs used, effective treatment of MDR-TB and XDR-TB still poses an important medical problem [7]. The low therapeutic efficacy of MDR-TB and XDR-TB treatment regimens makes the success resulting from using Lzd and Bq more obvious than in patients infected with MTB sensitive to the first-line ATDs [16]. Thus, the prescription of etiotropic treatment in patients with MDR-TB and XDR-TB should be personalized, taking into account the effectiveness and tolerability of each particular ATD [17].

The inclusion of Lzd and Bq in the postoperative chemotherapy regimen significantly reduced the duration of the course to 38.5±2.1 weeks compared with the control group, where this period was 44.6±2.2 weeks. Thus, the timing of a favorable outcome was reduced by 6.1 weeks (p<0.041).

The inclusion of Lzd and Bq in the postoperative chemotherapy regimen significantly reduces the course duration (down to 38.5±2.1 weeks) compared with the control group, where this duration was 44.6±2.2 weeks. Therefore, the onset of a favorable outcome occurred 6.1 weeks earlier (p<0.041). 

Higher therapeutic efficacy implies that the combination of Lzd and Bq with an optimized treatment regimen helps increase treatment adherence, and reduce the incidence of adverse effects and recurrence of the TB process.

An important aspect of chemotherapy, in addition to its duration, is high drug tolerance. The development of side effects can lead to a reduction in the dosage or to the complete withdrawal of drugs [16, 17]. 

Grade 1 adverse effects of the combined use of Lzd and Bq were noted in 24.1% (n=21) of cases; they were well corrected with medication and did not lead to a reduction in dosage or drug withdrawal. Our results are consistent with the results of other authors: the combined administration of Lzd and Bq was quite safe and had minor toxic effects, which were corrected without changing the dosage [7, 18]. Also, in other studies, the development of adverse events was noted during the first 12 weeks of the study. E.g., grades 2 and 3 adverse effects were reported by 5.6 to 20.5% of patients, which led to the need to reduce the dosage or discontinue ATDs [15].

At the same time, the above-mentioned research data were collected in patients receiving conservative treatment, including in combination with bronchial obstruction. 

Hence, in our study, the goals set in MDR-TB and XDR-TB chemotherapy were achieved due to timely correction of the treatment regimen, taking into account the results of examination of more informative biological material (resection material). In our study, the personalized approach to optimizing TB therapy via the combined administration of Lzd and Bq has met the expected safety and effectiveness criteria.

Conclusion

Inclusion of Lzd and Bq in the MDR-TB and XDR-TB chemotherapy regimen helps reduce the total duration of the treatment course until a favorable outcome by 6.1 weeks (p<0.041). The use of Lzd and Bq in postoperative chemotherapy is quite effective and safe. Although observed in 24.1% of patients, adverse effects were well controlled by medication and did not lead to a dosage reduction or drug discontinuation.

Author contributions. All authors contributed equally to the preparation of the manuscript.

Conflict of interest. No conflicts of interest are declared by the authors.