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  • Adverse Drug Reactions Associated with Isoniazid in Tuberculosis Patients: A Review Study

  • Photo Dinesh Kumar *

  • Pacific College Of Pharmacy, Paher University

Abstract

Tuberculosis (TB) is a communicable disease and one of the leading causes of death worldwide, caused by Mycobacterium tuberculosis .1, 2 Despite the availability of effective treatment, TB continues to be a major public health concern. Isoniazid is one of the most commonly used first-line antitubercular drugs due to its high efficacy and cost-effectiveness .7 However, its use is associated with various adverse drug reactions (ADRs), which may affect patient compliance and treatment outcomes .26The present review aims to evaluate the pattern, incidence, and types of adverse drug reactions associated with isoniazid therapy in tuberculosis patients. A comprehensive review of literature was carried out using previously published studies from different settings and populations. The findings suggest that a significant number of patients experience at least one ADR during the course of treatment.The most commonly reported adverse drug reactions include gastrointestinal disturbances, nausea, vomiting, hepatotoxicity, skin reactions, peripheral neuropathy, and fatigue. In some cases, severe adverse effects such as hepatitis and neurological complications have also been reported. It was observed that the majority of ADRs occur during the initial phase of treatment. 25, 26In conclusion, although isoniazid remains a cornerstone drug in tuberculosis management, careful monitoring of patients is essential for early detection and management of ADRs. Proper patient counseling and regular follow-up can improve treatment adherence and reduce the risk of complications, thereby enhancing the success of tuberculosis control programs

Keywords

Adverse Drug Reaction, Isoniazid in Tuberculosis

Introduction

Tuberculosis (TB) is a communicable disease that is a major cause of ill health and one of the leading causes of death worldwide. Until the coronavirus pandemic, TB was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. Tuberculosis is caused by a bacterium known as Mycobacterium tuberculosis. It spreads from person to person through the air when an infected individual coughs, sneezes, or sings, releasing tiny droplets containing the bacteria. These droplets can be inhaled by others, allowing the infection to enter the lungs. People living or working in crowded conditions are at higher risk of transmission.1, 2The total number of people who develop TB each year shows that approximately 90% are adults, with a higher prevalence among men than women. The disease most commonly affects the lungs (pulmonary TB) but can also involve other parts of the body. If left untreated, the death rate of TB is high (about 50%); however, with currently recommended treatment, about 85% of patients can be cured. Treatment regimens ranging from 1 to 6 months are available for TB infection .1Healthcare workers are at increased risk of Mycobacterium tuberculosis infection due to frequent exposure to patients with active pulmonary TB. Latent tuberculosis infection (LTBI) among healthcare workers has been reported to be as high as 64% worldwide. Approximately one-third of healthcare workers have been diagnosed with latent TB infection using interferon-gamma release assays, which is higher compared to other populations. Managing and treating LTBI in healthcare workers is important, as those who develop active TB can easily transmit the infection to patients. Additionally, individuals living with HIV have a significantly higher risk—about thirty times greater—of developing active TB compared to non-infected individuals .3, 4

HISTORY OF TUBERCULOSIS

Tuberculosis (TB) has been present in humans for thousands of years. The earliest evidence of TB was traced back to approximately 9,000 years ago in Atlit Yam, a submerged city off the coast of Israel. Historical records suggest that TB reached India around 3,300 years ago and China about 2,300 years ago. Mycobacterium bovis (bovine TB) is still found in many animals, including cattle and deer. Approximately 1 million cattle are tested annually for TB, and animals that come into contact with infected wildlife are at higher risk. In some cases, transmission of TB from animals to humans is also possible .5In the 1800s, physicians advised patients suffering from tuberculosis—then commonly known as “consumption”—to rest and consume nutritious food. It is an airborne disease that primarily affects the lungs, leading to symptoms such as persistent cough, fever, and chest pain .6In 2012, the Government of India declared TB a notifiable disease, similar to HIV, dengue, hepatitis B, malaria, polio, and chickenpox. This means that all diagnosed TB cases must be reported to government authorities. The Government also provides free treatment under a national program. The Revised National Tuberculosis Control Programme (RNTCP) was launched in 1997, and its treatment guidelines were later revised in 2010 .7

SYMPTOMS OF TUBERCULOSIS

Tuberculosis progresses through three stages: primary TB infection, latent TB infection, and active TB infection, with symptoms varying at each stage.Primary TB Infection:- This is the initial stage of infection. In most individuals, the immune system destroys the bacteria; however, some bacteria may survive and remain in the lungs. Many people do not show symptoms at this stage, while some may experience:

  1. Low-grade fever
  2. Fatigue
  3. Cough

Latent TB Infection: - In this stage, the immune system forms a protective barrier around the infected tissue in the lungs. The bacteria remain inactive and do not cause symptoms. However, they can become active later if immunity decreases.Active TB Infection: - This occurs when the immune system is unable to control the infection. Active TB may develop soon after primary infection or after a long period of latency. Common symptoms include:

  1. Persistent cough
  2. Coughing up blood or mucus
  3. Chest pain
  4. Pain during breathing or coughing
  5. Fever
  6. Chills
  7. Night sweats
  8. Weight loss
  9. Loss of appetite
  10. Fatigue
  11. General weakness

Extrapulmonary TB: - TB infection can also spread to other parts of the body. Symptoms depend on the affected site but commonly include:

  1. Fever
  2. Night sweats
  3. Weight loss
  4. Fatigue
  5. Pain at the affected site 2

RISK FACTORS OF TB INFECTION

Several factors increase the risk of developing tuberculosis infection:

  1. Living with a person who has active TB disease
  2. Living in or traveling to areas where TB infection is common
  3. Living or working in crowded conditions
  4. Belonging to a community identified as high risk for tuberculosis
  5. Working in healthcare settings and treating patients with TB

A weakened immune system significantly increases the risk of TB infection progressing to active disease. Conditions and factors that weaken the immune system include:

  1. HIV/AIDS
  2. Diabetes
  3. Severe kidney disease
  4. Cancers of the head, neck, and blood
  5. Use of illicit injectable drugs
  6. Alcohol misuse
  7. Smoking and use of other tobacco products 2

There are two main types of tests used for the detection of tuberculosis infection: the skin test and the blood test. Both tests help to determine whether a person has been infected with Mycobacterium tuberculosis, but they cannot differentiate between latent and active TB infection.

Skin Test: - The tuberculin skin test (Mantoux test) is the most commonly used test, especially in children under 5 years of age. It measures the immune response to a purified protein derivative (PPD) injected under the skin. PPD is a protein derived from Mycobacterium tuberculosis and does not contain live bacteria. If a person is infected, a firm red swelling appears at the injection site within 48–72 hours.

Blood Test: -The interferon-gamma release assay (IGRA) is a blood test used particularly for healthcare workers and immunocompromised individuals. In this test, a blood sample is taken and analyzed for the release of interferon-gamma in response to TB antigens.10

CHEST RADIOGRAPHY

Chest radiography is recommended for all individuals being evaluated for latent or active TB. Pulmonary TB typically presents with infiltrates in the upper lobes of the lungs, especially in the apical and posterior segments.11

SMEAR MICROSCOPY

Smear microscopy for the detection of acid-fast bacilli (AFB) is one of the most rapid and cost-effective methods for diagnosing tuberculosis .11

DIAGNOSIS OF TUBERCULOSIS

A complete evaluation for tuberculosis includes the following components:

  1. Medical history
  2. Physical examination
  3. Test for Mycobacterium tuberculosis infection
  4. Chest radiograph
  5. Bacteriological examination of clinical specimens

THE EFFECT OF TB STIGMA ON TB DIAGNOSIS OR TREATMENT

Tuberculosis (TB)-related stigma is widely considered to be a significant factor contributing to delays in diagnosis and negatively affecting treatment adherence. Several qualitative studies have reported that community members, TB patients, and healthcare providers perceive stigma as a major barrier to timely diagnosis and effective management of the disease.Individuals experiencing symptoms suggestive of TB may initially seek care from private healthcare providers in order to avoid social stigma. However, private healthcare facilities often have longer waiting times and higher costs, which may lead to delays in diagnosis and increased financial burden on patients.

Attempts to quantify the impact of TB stigma on diagnostic delay and treatment adherence have produced mixed results. Some studies have shown that stigma is not a significant predictor of delay in seeking healthcare. For example, studies conducted in Uganda, Zambia, and Syria found that factors such as daily alcohol use and socioeconomic conditions were more strongly associated with delays than perceived stigma. Nevertheless, stigma remains an important social factor that can influence health-seeking behavior and treatment outcomes in TB patients.12–21

First line drugs:-These drugs have high antitubercular efficacy as well as low toxicity; are use routinely.

DOSING OF ORAL FIRST-LINE ANTI-TB DRUGS22

 

Drug

Population

Daily Dose

Once Weekly

Twice Weekly

Thrice Weekly

Isoniazid

Adults (max)

5 mg/kg (300 mg)

15 mg/kg (900 mg)

15 mg/kg (900 mg)

15 mg/kg (900 mg)
 

Children (max)

10–20 mg/kg (300 mg)

N/A

20–40 mg/kg (900 mg)

N/A

Rifampin

Adults (max)

10 mg/kg (600 mg)

N/A

10 mg/kg (600 mg)

10 mg/kg (600 mg)
 

Children (max)

10–20 mg/kg (600 mg)

N/A

10–20 mg/kg (600 mg)

N/A

Rifabutin

Adults (max)

5 mg/kg (300 mg)

N/A

5 mg/kg (300 mg)

5 mg/kg (300 mg)
 

Children

10–20 mg/kg (300 mg)

N/A

10–20 mg/kg (300 mg)

10–20 mg/kg (600 mg)

Rifapentine

Adults

N/A

10 mg/kg (600 mg)

N/A

N/A
 

Children

N/A

N/A

N/A

N/A

Pyrazinamide

40–55 kg

1 g

N/A

2 g

1.5 g
 

56–75 kg

1.5 g

N/A

3 g

2.5 g
 

≥ 76 kg

2 g

N/A

4 g

3 g
 

Children (max)

15–30 mg/kg (2 g)

N/A

50 mg/kg (2 g)

N/A

Ethambutol

40–55 kg

800 mg

N/A

2000 mg

1200 mg
 

56–75 kg

1200 mg

N/A

2800 mg

2000 mg
 

≥ 76 kg

1600 mg

N/A

4000 mg

2400 mg
 

Children (max)

15–20 mg/kg (1 g)

N/A

50 mg/kg (2.5 g)

N/A

Moxifloxacin

≥ 12 years

400 mg

N/A

N/A

N/A

 

Notes:

  • Daily dosing refers to administration for 5–7 days per week.
  • Intermittent dosing (<7 days/week) should be given under directly observed therapy (DOT).
  • Rifapentine is used only in the continuation phase.
  • Maximum doses should not be exceeded.22

Second line drugs: - The drugs have either low antituberculosis efficacy or higher toxicity or both; and are use as reserve drugs.

  1. Ethionamide (Eto)
  2. Prothionamide (Pto)
  3. Fluroquinolones
  4. Cycloserine (Cs)
  5. Terizidone (Trd)
  6. Para-aminosalicyclic acid (PAS)
  7. Rifabutin
  8. Thiacetazone (Thz)
  9. Ofloxacin (Ofx)
  10. Levofloxacin (Lvx/Lfx)
  11. Moxifloxacin (Mfx)
  12. Ciprofloxacin (Cfx)

Injectable drugs

  1. Kanamycin (Km)
  2. Amikacin (Am)
  3. Capriomycin (Cm) 7, 3

ISONIAZID

Isoniazid is an antibacterial drug available in 100 mg and 300 mg tablets for oral administration. Each tablet contains inactive ingredients such as colloidal silicon dioxide, lactose monohydrate, pregelatinized starch, povidone, and stearic acid.The chemical name of isoniazid is isonicotinyl hydrazine or isonicotinic acid hydrazide. Its molecular formula is C?H?N?O, and its molecular weight is 137.4.Isoniazid is an odorless, colorless, or white crystalline powder. It is freely soluble in water, sparingly soluble in alcohol, and slightly soluble in chloroform and ether. It is slowly affected by exposure to air and light .23

MECHANISM OF ACTION OF ISONIAZID

Isoniazid is bactericidal against actively growing bacteria and bacteriostatic against resting bacteria. It acts as a prodrug and becomes active after entering the body.

  1. It is activated by the enzyme catalase-peroxidase (KatG).
  2. It is then converted into its active form, isonicotinic acyl.
  3. This active form combines with NADH to form a nicotinoyl-NAD complex.
  4. The complex binds to enoyl-acyl carrier protein reductase.
  5. This inhibits fatty acid synthesis and reduces the production of mycolic acid.
  6. Mycolic acid is an essential component of the mycobacterial cell wall.
  7. Inhibition of cell wall synthesis ultimately leads to the death of the bacteria.7

PHARMACOKINETICS24

  1. Isoniazid is completely absorbed after oral administration.
  2. It is widely distributed throughout body tissues.
  3. It is metabolized in the liver.
  4. It is primarily excreted through urine.

DRUG INTERACTIONS24

  1. Aluminium hydroxide reduces the absorption of isoniazid.
  2. The metabolism of benzodiazepines may be decreased when combined with isoniazid.
  3. Isoniazid may decrease the excretion rate of abacavir, leading to increased serum levels.
  4. The metabolism of drugs such as abemaciclib and acalabrutinib may be reduced.
  5. The therapeutic efficacy of acarbose may decrease when used with isoniazid.
  6. Drugs like aceclofenac and acemetacin may reduce the excretion of isoniazid, increasing its levels.

FOOD INTERACTIONS24

  1. Vitamin B6 (pyridoxine) supplementation is recommended to prevent deficiency.
  2. Alcohol consumption should be avoided, as it increases the risk of hepatitis and neuropathy.
  3. Foods containing tyramine (e.g., cheese, red wine, pickled foods) should be avoided.
  4. Chocolate and caffeine intake should be limited.
  5. Isoniazid should be taken on an empty stomach, either 1 hour before or 2 hours after meals.
  6. It should not be taken with antacids, as they reduce absorption.

ADVERSE EFFECTS OF ISONIAZID22

Adverse drug reactions (ADRs) associated with isoniazid may vary among individuals. Commonly reported ADRs include:

  1. Dizziness on sitting, standing, or lying down
  2. Loss of appetite
  3. Nausea and vomiting
  4. Stomach upset and heartburn
  5. Flu-like symptoms, with or without fever
  6. Severe fatigue or weakness
  7. Fever and chills
  8. Severe diarrhea or light-colored stools
  9. Dark-colored urine (brown or tea-colored)
  10. Yellow discoloration of skin or eyes (jaundice)
  11. Skin rash or itching
  12. Unexplained bruising or bleeding
  13. Shortness of breath
  14. Pain or tingling sensation in hands and feet

Although most patients tolerate the drug well, any occurrence of ADRs should be reported to a healthcare provider. The incidence of major adverse effects per month of treatment has been estimated to be 0.49% for isoniazid, 0.43% for rifampin, 1.48% for pyrazinamide, and 0.07% for ethambutol. However, cumulative toxicity may become significant, and ADRs can lead to discontinuation of treatment in approximately 11% of patients. Second-line antitubercular drugs are associated with a higher incidence of adverse effects.26

REVIEW OF LITRATURE

 

S. NO.

Title of Study

Type of Study Design

No of Participant Patient

Study Duration

Year of Study

Major outcome (Type of ADR)

27.

Drug Resistance in Tuberculous Lymphadenitis: Molecular Characterization

cross-sectional study

2018

2002-2020

2020

In the present study, 86% (43/50) of MTB isolates were sensitive to first-line anti-TB drugs, while 14% were resistant to at least one drug.

(Isoniazid-induced MDR-TB)

 

28.

Prevalence and Predictors of Pulmonary Tuberculosis among Prison Inmates in Sub-Saharan Africa: A Systematic Review and Meta-Analysis

 

Prospective study

72844

2006-2019

2020

TB/HIV co-infection, BMI, long duration of incarceration, and previous TB exposure were predictors of pulmonary TB. (Emphasizing)

29.

Antituberculosis Drug Nonadherence and Its Associated Factors: Evidence from Debre Berhan Town, North Shewa Zone, Ethiopia

 

Cross-sectional study

72844

1999-2022

2022

Strong monitoring and evaluation of anti-TB treatment services are required to improve adherence.

(Isoniazid influence on drug nonadherence)

30.

Assessment of Smear-Positive Pulmonary Tuberculosis and Associated Factors among Patients Visiting Health Facilities of Gedeo Zone, Southern Ethiopia: A Cross Sectional Study

 

Cross-sectional study

220

1 July – 30 Sep 2021

2023

The prevalence of smear-positive TB was 18.2%, with a GeneXpert detection rate of 29.5%.

(Isoniazid-induced DR-TB)

31.

Patient- and Health-System-Related Barriers to Treatment Adherence for Patients with Drug Resistant Tuberculosis in the Philippines: A Mixed-Methods Study

 

Prospective study

272

Dec 2017 – Mar 2018

2022

Patient- and health system-related barriers affect treatment adherence in DR-TB cases.

(Isoniazid-induced DR-TB)

32.

Tuberculosis therapy: past, present and future

Case study

78

2002

2002

Drug-susceptible TB can be cured in 6 months, but new strategies are needed for long-term control.

(Immune deficiency syndrome)

 

33.

Treatment Strategy for Rifampin Susceptible Tuberculosis

Prospective study

674

96 weeks

2023

Treatment duration varied across regimens, with shorter duration in newer strategies.

(Respiratory disability)

 

34.

A study of adverse drug reactions in tuberculosis patients in a tertiary care hospital

Retrospective study

480

18 months

2022

Routine monitoring and pharmacovigilance are important for TB program success.

(Gastrointestinal problems)

 

35.

Adverse drug reactions and associated factors in multidrug-resistant tuberculosis: A retrospective review of patient medical records at Mbarara Regional Referral Hospital, Uganda

 

Prospective study

178

January 2013 and

December 2020

2023

Most MDR-TB patients experienced at least one ADR during treatment.

(Ototoxicity)

36.

Assessing the prevalence and effect of adverse drug reactions among patients receiving first line anti-tubercular medicines in the Tamale Teaching Hospital, Ghana

 

cross-sectional descriptive study

66

Six month

2021

ADRs are common in first-line ATT, mainly gastrointestinal.

(GIT problems)

37.

Adverse drug reactions to first-line antituberculosis drugs at four DOTS centers in Goa, India

 

Prospective Study

186

October 2015 to September 2016

2023

Understanding ADRs improves treatment adherence and compliance.

(Hormonal variation)

38.

Characteristics and contributing factors of adverse drug reactions: an analytical study of patients with tuberculosis receiving treatment under the National TB Program of India

Case Study

593

3rd May 2021 to 30th July 2021

2022

Strengthening healthcare systems is necessary for ADR management.

(Skin-related problems)

39.

Adverse drug reactions in patients taking anti tuberculosis therapy from directly observed treatment short course centre at Mandya Institute of Medical Sciences, Mandya: a cross sectional study

 

Case Study

90

1 year

2018

Counseling and supervision reduce treatment default and drug resistance.

(Gastrointestinal manifestations)

40.

An Observational prospective study of Adverse Drug Reaction in new smear positive patient of Pulmonary Tuberculosis treated under directly observed treatment in continuous phase in general medicine OPD at Gulbarga Institute of medical science, Kalaburagi.

 

Prospective study

180

2 weeks

2018

ADR incidence was 57.7%, with GI irritation most common.

(Jaundice)

41.

Incident and Pattern of Adverse Drug Reaction in Patients treated for Tuberculosis under Dots at a tertiary care hospital of Northern India

 

Case study

115

12 month

2018

58.26% of patients developed ADRs, mostly in middle age groups.

(Ototoxicity)

42.

Adverse Drug Reactions of Anti-Tuberculosis Treatment among Children with Tuberculosis

 

Prospective Study

508

June 2016 to November 2016

2020

13.2% of children experienced ADRs, while most had none.

(Arthralgia)

43

Adverse Drug Reactions to a Daily Fixed-dose Combination Based Antituberculosis Treatment Regime in India’s National Tuberculosis Elimination Programme: A Prospective Cohort Study

 

Prospective cohort study

706

January 2019 to September 2020

2022

ADRs were observed among patients with demographic variations.

(Joint pain)

44.

Adverse Drug Reaction among Drug resistance Tuberculosis treatment: An observation cohort study

 

Prospective cohort study

146

2016 to 2019

2021

ADRs are often underreported; long treatment and comorbidities increase risk.

(Vomiting)

45.

Associations between the Adverse Drug Reactions and the Tuberculosis Treatment Dropout Rates at the Cempaka Putih Islamic Hospital in Jakarta, Indonesia

 

Case study

178

Jan 2016 to Dec 2017

2020

High treatment dropout rate associated with ADRs and demographic factors.

(Nausea)

46.

Analysis of burden and outcomes of anti-tuberculosis therapy-induced adverse drug effects at a tertiary care center

 

Prospective study

164

June 2017 to December 2018

2022

27.4% of patients developed ADRs, some severe.

(Anorexia)

47.

Adverse Drug Reactions in Patients on Second Line Anti-Tubercular Drugs for Drug Resistant Tuberculosis in Rural Tertiary Care Hospital in North India

 

Prospective study

104

1st November 2012 to 31st October 2013

2018

ADRs commonly occurred within 2–3 months of therapy.

(Arthralgia)

48.

Incidence of adverse drug reactions in patients taking anti-tuberculosis treatment

 

Prospective study

108

March 2007 - April 2008

2019

25.9% experienced ADRs, mainly GIT intolerance, hepatitis, and skin reactions.

(Hepatitis)

49.

Adverse Drug Reactions Monitoring In Patients On Antitubercular Treatment in Tertiary Care Hospital, Mandya

 

Prospective Study

74

6 months

2021

ADRs were most common in the 31–40 age group with low BMI.

(Gastrointestinal problems)

50.

Adverse drug reactions during drugresistant TB treatment in high HIV prevalence settings: a systematic review and meta-analysis

 

Systematic review & meta-analysis

2776

24 month

2017

83% of patients experienced ADRs during DR-TB treatment.

(Hypothyroidism)

51.

Adverse drug reactions associated with first line anti-tubercular drugs, their prevalence and causality assessment in patients on Directly Observed Treatment Short-course (DOTS) in a tertiary care hospital

 

Cross-sectional study

164

9 month

2018

Pharmacovigilance improves safety and treatment outcomes.

(Isoniazid-induced liver problems)

52.

Evaluation of anti-tuberculosis induced adverse reactions in hospitalized patients

 

Case series

83

July 2001 to July 2002

2026

Anti-TB drugs may cause severe ADRs leading to hospitalization.

(Liver injury)

53.

A study on adverse drug reactions to first line antitubercular drugs in DOTS therapy

 

Prospective Study

511

July 2013 to November 2013

2015

Patient education improves ADR reporting and adherence.

(Hepatitis)

54.

Adverse drug reactions and associated factors in multidrug-resistant tuberculosis: A retrospective review of patient medical records at Mbarara Regional Referral Hospital, Uganda

 

Retrospective Study

178

January 2013 and

December 2020

2023

Shorter regimens may still cause intolerable ADRs.

(Respiratory failure)

55.

Factors associated with adverse drug reactions or death in very elderly hospitalized patients with pulmonary tuberculosis

 

Retrospective study

632

60 days

2023

Careful monitoring is required in elderly TB patients.

56.

Adverse Drug Reactions to AntiTuberculous Drugs–A Survey of Perceptions and Practices of Physicians in a Singaporean Tertiary Centre

 

Prospective study

45

29 August to 12 September 2017

2018

ADR management remains challenging; better clinical guidance is needed.

(Respiratory failure)

57.

A Study on Incidence of Adverse Drug Reaction of Anti-Tubercular Drugs in New Cases of Pulmonary Tuberculosis in a Tertiary Care Teaching Hospital Article History

 

Prospective Study

263

12 month

2016

The major detection of adverse drug reactions was from the gastrointestinal system. The majority of ADR causality was probable (74.52%), followed by possible (19.81%) and definite (5.67%).

(Arthralgia)

58.

Adverse drug reaction monitoring of antitubercular drugs during intensive phase at tertiary care medical college hospital: A prospective study

Prospective Study

100

6 months

2020

Among 100 pulmonary TB patients receiving fixed-dose combination therapy, the most common ADRs were nausea (20 cases), hepatitis (19 cases), and gastritis (15 cases), along with pruritus, abdominal cramps, and diarrhea.

(Abdominal cramps)

59.

Prevalence of adverse drug reaction with first-line drugs among patients treated for pulmonary tuberculosis

 

Prospective study

893

8 Months

2015

TB treatment can cause a variety of ADRs. Accurate diagnosis and knowledge of drug pharmacology help in individualized patient management.

(Psychiatric disorders)

60.

Adverse Drug Reactions Related to Treatment of Drug-Susceptible Tuberculosis in Brazil: A Prospective Cohort Study

 

Prospective Cohort Study

606

2010 to 2016

2022

78.8% of patients experienced at least one ADR during TB treatment. Other studies in Brazil reported ADR incidence ranging from 23.6% to 83.4%. (Hepatotoxicity)

61.

Adverse reactions to antituberculosis drugs in Man guinhos, Rio de Janeiro, Brazil

 

Case study

370

2002-2008

2012

The most affected systems were gastrointestinal (29.4%), skin (21.4%), nervous system (14.3%), and musculoskeletal system (10.3%).

(Sweat and urine turning orange)

62.

Adverse Drug Reactions and Outcome of Short Course Anti Tuberculosis Drugs between Single Daily Dose and Split Drug Dose (BID) in Pulmonary Tuberculosis

 

Case study

122

6 months

2012

Patients receiving split drug regimens showed a higher cure rate compared to once-daily dosing, although the difference was not statistically significant.

(Anorexia)

63.

Adverse Drug Reaction in Treatment of Multidrug Resistant Tuberculosis

 

Prospective cohort study

98

June 2009 to Feb 2010

2013

The most frequent ADRs were nausea/vomiting (24.5%), hearing disturbances (12.3%), dizziness/vertigo (10.2%), and arthralgia (9.2%).

(Hearing disturbances)

64.

Adverse events among patients of multi drug resistant tuberculosis receiving second line anti TB treatment

 

Prospective Study

310000

1 year

2012

ADRs are more common in MDR-TB patients receiving second-line therapy. Counseling, proper drug spacing, and a high-protein diet help improve tolerance and reduce default rates.

(Renal dysfunction)

65.

Adverse Drug Reactions with First Line and Second-Line Drugs in Treatment of Tuberculosis

 

Retrospective cohort study

98

8 months

2021

Most ADRs can be managed successfully on an outpatient basis, even in resource-limited settings. (Psychiatric disorders)

66.

Impact of the change in the antitubercular regimen from three to four drugs on cure and frequency of adverse reactions in tuberculosis patients from Brazil: A retrospective cohort study

 

Retrospective cohort study

730

January 2007 and December 2014

2019

Treatment interruption and changes in drug regimens due to ADRs were similar between different treatment groups.

(Gastrointestinal disorder)

67.

A Study of Adverse Drug Reactions in Tuberculosis Patients in a Tertiary Care Hospital

Cross-sectional, prospective study

480

2 months

2022

Out of 480 patients, 25% developed ADRs. ADRs were more common in males and adults. The gastrointestinal tract was most affected (39%), followed by generalized disorders (19%) and hepatobiliary system (17%). Most ADRs occurred within 0–2 months.

(Joint pain/arthralgia)

68.

A Study of Adverse Drug Reactions Caused by Second Line Anti Tubercular Drugs Used in Nepal

 

Case study

366

8 month

2015

MDR-TB treatment caused ADRs of varying severity. Males showed a higher incidence. Most ADRs were mild and had a possible relationship with drugs.

(Gastrointestinal disorder)

69.

A Profile of Adverse Effects of Anti Tubercular Drugs

 

prospective observational study

974

2007 - 2008

2016

Severe side effects of anti-TB drugs are common, especially in pulmonary TB patients, requiring close monitoring.

(Giddiness)

70.

A study of adverse drug reactions in patients receiving treatment for multidrug-resistant tuberculosis in a tertiary care center

 

prospective cross-sectional observational study

148

July 2018 to June 2019

2021

Out of 148 patients, 112 developed at least one ADR, with a total of 15 different types reported.

(Headache)

71.

Safety Profile of Medicines Used for the Treatment of Drug-Resistant Tuberculosis: A Descriptive Study Based on the WHO Database (VigiBase((R))

 

Case study

349831

January 2018 to December 2020.

2023

Among reported drugs, pyrazinamide was most commonly associated with ADRs, followed by ethionamide and cycloserine.

(Nervous system disorders)

72.

Impact of adverse drug reaction and predictivity of quality of life status in tuberculosis

 

Retrospective study

104

2005 and 2006

2006

Some unmeasured confounding factors may influence ADR outcomes despite controlling for major sociodemographic variables.

(Gastrointestinal disorder)

73.

The Burden of Bacteriologically Negative TB Diagnosis: A Four-Year Review of Tuberculosis Cases at a Tertiary Facility

 

Retrospective Study

1,933

January 2017 and December 2020

2023

Among 1,933 TB patients, the majority were new cases, with a high proportion in the 24–64 age group. Pulmonary and extrapulmonary TB were almost equally distributed.

(Abdominal pain)

74.

Prevalence and Predictors of Pulmonary Tuberculosis among Prison Inmates in Sub-Saharan Africa: A Systematic Review and Meta-Analysis

 

Meta Analysis

3,479

2006 to 2019

2023

Underweight status, TB/HIV co-infection, long incarceration, and previous exposure were predictors of TB among prisoners.

(Gastrointestinal)

75.

Drug induced Hepatotoxicity Anti Tuberculosis drugs therapy: A case report.

 

Systematic review and meta-analysis

1

15 days

2019

Drug-induced hepatotoxicity occurred after 15 days of anti-TB therapy, with elevated bilirubin and liver enzyme levels.

(Hepatotoxicity)

76.

Hepatitis Induced by Anti-Tubercular Therapy and Chronic Alcoholism: A Case Report

 

Case report

1

10 days

2019

The patient developed hepatotoxicity and severe alcohol-induced hepatitis after receiving first-line anti-TB drugs.

(Hepatotoxicity)
 

CONCLUSION

In this review, the incidence of adverse drug reactions (ADRs) was found to be at least one in the majority of patients. The maximum number of patients included in the reviewed articles was 424,203, while the minimum number was 1. After analyzing these studies, the most commonly reported ADRs were:

  • Gastrointestinal disturbances
  • Night sweats
  • Nausea and vomiting
  • Rashes
  • Multidrug-resistant tuberculosis (MDR-TB)
  • Respiratory disorders
  • Otitis
  • Hormonal variations
  • Skin-related problems
  • Jaundice
  • Ototoxicity
  • Arthralgia and joint pain
  • Anorexia
  • Hepatitis
  • Hypothyroidism
  • Abdominal pain
  • Psychiatric disorders
  • Discoloration of sweat and urine
  • Hearing disturbances
  • Renal dysfunction
  • Giddiness
  • Headache
  • Nervous system disorders

The majority of adverse drug reactions occurred during the initial phase of treatment. Therefore, conducting regular and thorough follow-up of patients during this phase can help in early recognition and appropriate management of ADRs. This will improve patient compliance and confidence in the Revised National Tuberculosis Control Programme (RNTCP), ultimately contributing to its success.With the increasing prevalence of drug-resistant tuberculosis, it is essential to create awareness among DOT providers, healthcare workers, patients, and family members regarding the importance of early detection of ADRs. Strict monitoring of therapy should be ensured to prevent treatment noncompliance and negligence. Efforts should also be made to develop new anti-tubercular drugs and strengthen pharmacovigilance systems to reduce treatment duration and improve safety.It was also observed that a lack of awareness about national tuberculosis programs and public health facilities may lead to negative perceptions of public healthcare services. This can make it difficult for economically weaker patients to access proper treatment. Additionally, some TB patients prefer private healthcare services due to concerns regarding the quality of care and medications available in public health facilities.

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Reference

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  3. Sung JunChung, Hyun Lee and GunWoo Koo: Adherence to nine-month isoniazid for latent tuberculosis infection in healthcare workers: a prospective study in a tertiary hospital, (2020) 10:6462
  4. Juliet Addo and Dave Pearce: Living with tuberculosis: a qualitative study of patients’ experiences with disease and treatment, (2022) 22:1717.
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  28. M B Habtamu, W Fasil and A Yibeltal: Prevalence and Predictors of Pulmonary Tuberculosis among Prison Inmates in Sub-Saharan Africa: A Systematic Review and Meta-Analysis https://doi.org/10.1155/2023/6226200.
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  30. M Bahru, S Gizaw and A Ephrem: Assessment of Smear-Positive Pulmonary Tuberculosis and Associated Factors among Patients Visiting Health Facilities of Gedeo Zone, Southern Ethiopia: A Cross-Sectional Study Volume 2023, Article ID 2502314, 7 pages https://doi.org/10.1155/2023/2502314.
  31. E Yutaka, J Jahn and P Rajendra: Patient- and Health-System-Related Barriers to Treatment Adherence for Patients with Drug-Resistant Tuberculosis in the Philippines: A Mixed-Methods Study. Volume 2022, Article ID 6466960, 11 pages https://doi.org/10.1155/2022/6466960.
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  34. L. Shilpa and Todkar: A study of adverse drug reactions in tuberculosis patients in a tertiary care hospital. https://dx.doi.org/10.18203/2319- 2003.ijbcp20222748 . pISSN 2319-2003 | eISSN 2279-0780.
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  40. R Dayanand: An Observational prospective study of Adverse Drug Reaction in new smear positive patient of Pulmonary Tuberculosis treated under directly observed treatment in continuous phase in general medicine OPD at Gulbarga Institute of medical science, Kalaburagi. 2018; 5(32), 2360- 2363. DOI: 10.18410/jebmh/2018/487.
  41. T Sachin: Incidence and pattern of Adverse Drug Reaction in Patient treated for Tuberculosis under dots at a tertiary care hospital of Northern India. 10.13040/IJPSR.0975-8232.9(11).4950-55.
  42. L Madeeha: Adverse Drug Reactions of Anti-Tuberculosis Treatment among Children with Tuberculosis. https://orcid.org/0000-0002-5047-9254.
  43. M Kapil: Adverse Drug Reactions to a Daily Fixed-dose Combination Based Antituberculosis Treatment Regime in India’s National Tuberculosis Elimination Programme: A Prospective Cohort Study. 2022 Aug, Vol-16(8): OC14-OC19.
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  51. N Tauseef: Adverse drug reactions associated with first line anti-tubercular drugs, their prevalence and causality assessment in patients on Directly Observed Treatment Short-course (DOTS) in a tertiary care hospital. DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20185174 .
  52. G Kheirollah: Evaluation of anti-tuberculosis induced adverse reactions in hospitalized patients.
  53. Athira B, Manju CS, Jyothi E. A study on adverse drug reactions to first line antitubercular drugs in DOTS therapy. Int J Pharmacol and Clin Sci 2015;4:7-11.
  54. K Oliver: Adverse drug reactions and associated factors in multidrug-resistant tuberculosis: A retrospective review of patient medical records at Mbarara Regional Referral Hospital, Uganda. DOI: 10.1177/20503121231171350 journals.sagepub.com/home/smo.
  55. Y Mitsuaki: Factors associated with adverse drug reactions or death in very elderly hospitalized patients with pulmonary tuberculosis. | https://doi.org/10.1038/s41598-023-33967-6.
  56. S. Zheng: Adverse Drug Reactions to Anti-Tuberculous Drugs–A Survey of Perceptions and Practices of Physicians in a Singaporean Tertiary Centre. https://doi.org/10.1016/j.ijid.2018.04.4201.
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Dinesh Kumar
Corresponding author

Pacific College Of Pharmacy, Paher University .

Dinesh Kumar, Adverse Drug Reactions Associated with Isoniazid in Tuberculosis Patients: A Review Study, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 2822-2843, https://doi.org/10.5281/zenodo.19629342

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