THE FREQUENCY AND CHARACTERISTICS OF ADVERSE REACTIONS TO ANTI-TUBERCULOSIS DRUGS IN PATIENTS WITH DRUG-RESISTANT PULMONARY TUBERCULOSIS

ABSTRACT

Drug-resistant tuberculosis (DR-TB) remains one of the most pressing problems in modern phthisiology, due to the length of treatment, limited choice of effective treatment regimens, and high incidence of side effects from reserve anti-tuberculosis drugs. The aim of the study was to investigate the frequency, nature, severity, and timing of side effects in patients with drug-resistant pulmonary tuberculosis. A retrospective analysis of the medical records of 109 patients who received a modified shortened treatment regimen for MDR-TB at the Regional Phthisiopulmonology Center in Karaganda in 2020–2023 was conducted. Adverse drug reactions, their clinical manifestations, severity, and time of onset during therapy were evaluated. Side effects were identified in 21% of patients, with myelosuppression, convulsive syndrome, and QT prolongation being the most frequently reported. Most adverse reactions occurred in the first weeks and the first month of treatment and were predominantly mild in severity, more often associated with the use of linezolid and cycloserine. The results obtained indicate a significant impact of side effects on the course of LUTB therapy and emphasize the need for their early detection, timely correction, and constant monitoring of patients' condition to improve the effectiveness and safety of treatment.

АННОТАЦИЯ

Лекарственно-устойчивый туберкулез (ЛУТБ) остаётся одной из наиболее актуальных проблем современной фтизиатрии, что связано с длительностью лечения, ограниченным выбором эффективных схем терапии и высокой частотой побочных эффектов резервных противотуберкулезных препаратов. Целью исследования явилось изучение частоты, характера, степени тяжести и сроков возникновения побочных эффектов у пациентов с лекарственно-устойчивым туберкулезом лёгких. Проведён ретроспективный анализ медицинской документации 109 пациентов, получавших модифицированную сокращённую схему лечения ЛУТБ в Областном фтизиопульмонологическом центре г. Караганды в 2020–2023 гг. Оценивались нежелательные лекарственные реакции, их клинические проявления, выраженность и время появления в ходе терапии. Побочные эффекты были выявлены у 21% пациентов, наиболее часто регистрировались миелосупрессия, судорожный синдром и удлинение интервала QT. Большинство нежелательных реакций возникало в первые недели и первый месяц лечения и преимущественно были лёгкой степени тяжести, чаще ассоциируясь с применением линезолида и циклосерина. Полученные результаты свидетельствуют о значимом влиянии побочных эффектов на течение терапии ЛУТБ и подчёркивают необходимость их раннего выявления, своевременной коррекции и постоянного мониторинга состояния пациентов для повышения эффективности и безопасности лечения.

Keywords: drug-resistant tuberculosis, anti-tuberculosis drugs, adverse drug reactions.

Ключевые слова: лекарственно-устойчивый туберкулез, противотуберкулезные препараты, побочные эффекты.

The frequency and nature of adverse reactions to anti-tuberculosis drugs in patients with drug-resistant pulmonary tuberculosis

Introduction

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which remains one of the leading causes of morbidity and mortality worldwide today. According to the World Health Organization (WHO), approximately 1.25 million people die from this disease each year [1-3]. Kazakhstan ranks 8th among the 20 countries with the highest prevalence of multidrug-resistant tuberculosis (MDR-TB). Treatment of XDR-TB with second-line drugs is characterized by an increased incidence of adverse effects, which is significantly higher compared to first-line treatment regimens [4].

According to WHO recommendations, tuberculosis treatment requires the use of long-term, combination chemotherapy involving 4–5 drugs. Such a prolonged treatment course increases the risk of developing numerous adverse drug reactions. According to the WHO definition, a drug-induced adverse reaction (DIAR) is an undesirable and harmful reaction that occurs in the body when a drug is used at a normal dose for prevention, diagnosis, or treatment [4,5].

Adverse drug reactions (ADRs) developing during anti-tuberculosis therapy reduce treatment efficacy and negatively affect the patient's overall condition. Side effects can worsen the prognosis of the disease, leading to disability or death. Therefore, the prevention and timely correction of ADR during anti-tuberculosis therapy is a relevant issue in the field of pulmonology [6,7].

Research Objective

To determine the frequency, nature, and severity of adverse effects resulting from the use of anti-tuberculosis drugs in patients with drug-resistant pulmonary tuberculosis (DRPT).

Materials and Methods

For the study, the medical records of patients with drug-resistant pulmonary tuberculosis (DRPT) treated at the Regional Tuberculosis and Pulmonology Center in Karaganda from 2020 to 2023 were reviewed.

These patients were treated with a modified regimen in accordance with the Order No. 214 of the Ministry of Health of the Republic of Kazakhstan from 2020. This treatment is intended for patients with rifampicin-resistant or multidrug-resistant tuberculosis who have not previously received second-line anti-tuberculosis drugs or have received them for less than one month.

Patients received treatment according to two different regimens:

Regimen 1: levofloxacin (Lfx), bedaquiline (Bdq), linezolid (Lzd), clofazimine (Cfz), cycloserine (CS);

Regimen 2: levofloxacin (Lfx), bedaquiline (Bdq), linezolid (Lzd), clofazimine (Cfz), delamanid (Dlm).

Of the 109 patients included in the analysis, 65.1% (n=71) were men and 34.8% (n=38) were women. The patients' mean age was 42 ± 12.3 years.

The data were processed using Microsoft Excel 2021 and version 23.12 of the MCO program.

Results

The development of adverse effects was recorded in 23 of 109 patients (21%). Of these, 12 were women (11%) and 11 were men (10%). Co-morbidities were identified in 56.5% (n=13) of patients who developed adverse effects. The most common of these were hepatitis C (38.4%), peripheral neuropathy (30.7%), and type 2 diabetes (30.7%), arterial hypertension (23%), ischemic heart disease (15.3%), as well as open-angle glaucoma, alcoholism, left kidney carcinoma, and secondary cardiomyopathy in individual cases (7.7% each).

Four patients experienced two or more adverse effects, while adverse reactions to two or more medications were identified in seven patients.

Among the 18 patients treated with regimen 1, there were 10 women (55.5%) and 8 men (44.4%). Among the 5 patients treated with Scheme 2, there were 2 women (40%) and 3 men (60%).

The following adverse effects were identified based on laboratory and instrumental studies: myelosuppression, elevated ALT and AST levels, QT interval prolongation, duodenal ulcer, MCS (multi-organ inflammatory syndrome), psychosis, seizures, depression, allergic reactions.

In patients treated with regimen 1, side effects occurred with the following frequencies: myelosuppression – 61.1%, seizures – 16.6%, QT prolongation – 11.1%, ALT/AST elevation – 5.5%, hepatitis – 5.5%, ulcer – 5.5%, psychosis – 5.5%. (Figure 1)

In Scheme 2, myelosuppression was observed in 40% of cases, seizures in 20%, depression in 20%, and allergic reactions in 20%. (Figure 2)

Analysis of the drugs revealed that adverse effects were most frequent with linezolid (schedule 1 – 40.5%; schedule 2 – 40%) and cycloserine (schedule 1 – 21.6%; in Scheme 2 – 40%) were recorded. Rare side effects were associated with levofloxacin (16.2%), bedaquiline (13.5%), and clofazimine (8.1%).

The majority of adverse events developed in the first weeks (40%) (Table 2) and the first month (33.3%) (Table 1) after starting the DAA regimen.

In Scheme 1, 77.5% of adverse events were mild, 27.6% were moderate, and 5.5% were severe. Mild reactions included myelosuppression, QT prolongation, and ulcers; moderate severity included elevated ALT and AST, hepatitis; severe included seizures and psychosis. (Table 3.1 )

In Scheme 2, mild side effects predominated (60%), while moderate-severity reactions (seizures, depression) were recorded in 40% of cases. (Table 4 )

Figure 1. Frequency of adverse effects reported in patients treated with treatment regimen 1

Figure 2. Adverse effects recorded in patients treated with 2 treatment regimens

Table 1.

Analysis of the appearance time of adverse drug reactions in patients treated with 1 treatment regimen

Table 2.

Analysis of the duration of visual acuity restoration in patients treated with treatment regimen 2

Table 3.

The target for assessing the severity of heart failure in patients receiving the treatment regimen

Table 4.

Target for assessing the severity of drug side effects in patients receiving the treatment regimen

Conclusion. According to the study's results, side effects were recorded in 21% of patients with drug-resistant pulmonary tuberculosis as a result of using TBIs.

In Scheme 1, hematological disorders were frequently observed, and the vast majority were mild. In Scheme 2, myelosuppression was recorded alongside psychoneurological and allergic manifestations.

The drug that caused the most side effects was linezolid (40.5%). In some patients, side effects developed simultaneously with multiple drugs.

Early detection of adverse reactions to QTX, assessment of their severity, and timely correction are key conditions for conducting effective chemotherapy and achieving the patient's clinical recovery.

References:

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3. Order of the Minister of Health of the Republic of Kazakhstan dated November 30, 2020 No. ҚР ДСМ-214/2020. On the approval of rules for conducting tuberculosis prevention measures https://adilet.zan.kz/rus/docs/V2000021695
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