Review article
Adverse drug reactions in tuberculosis and management

https://doi.org/10.1016/j.ijtb.2019.11.005Get rights and content

Abstract

Background

Treatment of drug susceptible tuberculosis (DS-TB) requires regimens containing first line drugs (FLDs’) whereas drug resistant tuberculosis (DR-TB) are treated with regimens comprising combination of both second line drugs (SLDs’) and few FLDs’. Adverse drug reactions (ADRs’) to these anti-tubercular drugs are quite common as they are being used for longer duration. ADRs’ may cause associated morbidity and even mortality if not recognized early. There are major concerns regarding treatment of DR-TB patients particularly with SLDs’ in that they are expensive, have low efficacy and more toxic as compared to FLDs’. There may be a severe impact on adherence and higher risk of default and treatment failure affecting outcome overall if such ADRs’ are not properly managed.

Methods

A search strategy was adopted involving principal electronic databases (Pubmed, EMBASE, Google and Google scholar) of English language articles from 1990 till now, using various terms in combination. All articles with resulting titles, abstract and full text, when available were read and kept for reference.

Results

101 articles including 4 systematic reviews have been identified. The overall prevalence of ADRs’ with FLDs’ and SLDs’ are estimated to vary from 8.0% to 85% and 69% to 96% respectively. Most ADRs’ are observed in the intensive phase as compared to continuation phase. No difference in frequency of ADRs’ was reported with intermittent or daily intake of anti-tubercular drugs. The occurrence of ADRs’ may be influenced by multiple factors and may range from mild gastrointestinal disturbances to serious hepatotoxicity, ototoxicity, nephrotoxicity peripheral neuropathy, cutaneous ADRs’, etc. Most of ADRs’ are minor and can be managed without discontinuation of treatment. Some ADRs’ can be major or severe causing life-threatening experience leading to either modification or discontinuation of regimen and even mortality if not recognized and treated promptly.

Conclusion

Early recognition by active surveillance and appropriate management of these ADRs’ might improve adherence and treatment success.

Introduction

India features among the 22 high tuberculosis (TB) burden countries and has accounted for an estimated one-quarter (26%) of all TB cases worldwide.1 Treatment regimen comprising multiple first-line drugs (FLDs') such as Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) and Streptomycin (S), remains the cornerstone of treatment of drug-susceptible TB (DS-TB) whereas second line drugs (SLDs') are reserved for treatment of drug-resistant TB (DR-TB). Good bacteriological diagnosis and compliance on treatment are the two main pillars of successful treatment of TB. The World Health Organization (WHO) has defined adverse drug reactions (ADRs') as ‘‘A response to a drug which is noxious and unintended, and which occurs at doses normally used in human for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.’’2 Patients may experience a variety of ADRs' when managed with these anti-tubercular drugs. Treatment with these drugs can also be associated with adverse events which is defined as any untoward medical occurrence but not necessarily have a causal relationship. ADRs' to these agents are common and cause significant morbidity and even sometimes mortality if not detected early.3, 4, 5 Most of ADRs' are minor and can be managed without discontinuation of treatment. Some can be serious or major causing life-threatening experience leading to either shorter or prolonged hospitalization, significant disability, congenital anomaly or even mortality if unrecognized and untreated promptly. Timing, the pattern of illness, the results of investigations, and re-challenge will help attribute causality to a suspected ADR.6 Various factors such as the dose and time of day at which the medication is administered, patient age, nutritional status, the presence of pre-existing diseases or dysfunctions like impaired liver function, impaired kidney function, human immunodeficiency virus (HIV) co-infection, and alcoholism may be related to ADRs' to anti-tubercular drugs.7 This calls for continued surveillance of ADRs' particularly in patients having DR-TB where early recognition and appropriate management of ADRs' might determine favourable outcome. This review aims to highlight the estimated burden and management strategies of various ADRs' associated with anti-tubercular drugs among patients undergoing treatment of TB.

Section snippets

Prevalence of adverse drug reactions treated with first line anti-tubercular drugs: global scenario

The data on global prevalence of ADRs' with FLDs' are scarce. The prevalence of ADRs' observed in various studies conducted worldwide ranged from 8% to 85%.3,8, 9, 10, 11, 12, 13, 14, 15 The reasons for the difference in the prevalence of ADRs' across these studies might be related to several possible factors such as: differences in definitions of ADRs' terminologies as adopted by physicians, whether the ADRs' were reported by patient (subjective) or detected by clinician (objective) on the

Prevalence of adverse drug reactions treated with second line anti-tubercular drugs: global scenario

The management of MDR-TB patients has been considered to be complicated and challenging because of prolonged duration of 24–27 months of treatment and high toxicity profile of SLDs'. The prevalence of ADRs' observed in various studies conducted worldwide ranged from 69% to 96%.18, 19, 20, 21, 22, 23, 24, 25 Reasons for the difference in the prevalence of ADRs' across these studies is almost similar to that of FLDs'. However, diversity can also be due to the fact that regimens for DR-TB contains

Prevalence of adverse drug reactions treated with first-line anti-tubercular drugs: India

The overall prevalence of ADRs' with FLDs' is estimated to vary from 2.3% to 17% in various Indian studies.8,26, 27, 28 A study conducted by Mehrotra et al observed that the prevalence of ADRs' in the initial intensive phase was 17.39%.26 Another study conducted at a tertiary institute in Calcutta observed that the overall toxicity was found in 35% cases in the daily regimen group, whereas it was found to be 27.9% in the intermittent regimen group.29 Data regarding prevalence of ADRs’ are still

Prevalence of adverse drug reactions treated with second line anti-tubercular drugs: India

Very few have specifically reported frequency of ADRs' in India.18,30, 31, 32, 33, 34, 35, 36, 37 A study conducted in Tamil Nadu by Joseph P et al reported ADRs' associated with standardized treatment in 86.8% patients.31 Severe ADRs' requiring either a reduction of dosage or termination of the offending drug(s) such as ethionamide (Eto), Ofx, Km and Cs were observed in 58% patients. Another study conducted in Mumbai among 67 HIV and MDR-TB co-infected patients treated with anti-TB treatment

Gastrointestinal adverse drug reactions

Gastrointestinal symptoms are one of the most common ADRs' seen with intake of anti-tubercular drugs. Its severity can range from mild symptoms like nausea, vomiting to life-threatening complications. All the FLDs' can cause mild gastrointestinal upsets that can be managed symptomatically without change in dosage of drugs. In a study of 893 patients by Shinde et al, it was found that gastrointestinal upset with nausea, vomiting, and abdominal pain were the most common ADRs' seen in 12.5% of

Hepatotoxicity

The clinical presentation of anti-tubercular drug associated hepatitis is similar to that of acute viral hepatitis. Anti-tubercular drug induced hepatotoxicity can manifest as transitory asymptomatic rise in transaminases or acute liver failure. The frequency of hepatotoxicity ranges from 2% to 39% in different countries.40 An increased incidence of hepatotoxicity has been observed in Indian sub-population when compared to Western population.41,42 Drug induced hepatotoxicity in Indian

Peripheral neuropathy

Peripheral neuropathy occurs in approximately 20% of patients treated with H.56 This was similar to findings of a study in Pakistan where peripheral neuropathy characterized by tingling and burning sensation in the hands and feet was the most common ADR observed with H. The other anti-TB drug known to cause peripheral neuropathy is E, but very rare in comparison to H. In a study conducted by Koju et al, peripheral neuropathy was experienced by only 18.57% of the patients.57 In the existing

Psychiatric disorders

H-related psychiatric disorders can manifest as psychosis, obsessive-compulsive neurosis, seizure, mania, loss of memory and death.60 The first description of psychotic symptoms due to H was by Mandel et al, who reported three such cases in 1956.61 The mechanism of production of H-related psychiatric disorders is not clearly known, but H is known to interfere with several metabolic processes essential for the normal functioning of the neuron. H causes deficiency of vitamin B6 by causing

Optic/retrobulbar neuritis

E is one of the important FLDs' in the treatment of TB. Carr and Henkind et al first described the ocular ADRs' of E therapy in 1962.65 Retro-bulbar neuritis is the most important potential ADR from E. It is reversible in most cases and is related to the dose and duration of treatment, but may occasionally become irreversible resulting in permanent visual disability, especially in the older population.66 The reported incidence of retro-bulbar neuritis when E is taken for more than 2 months is

Ototoxicity

Streptomycin (S) predominantly affects the vestibular system whereas Km and Cm affects predominantly cochlear apparatus. Audiometry data suggest that the incidence of S associated ototoxicity may be as high as 25%.71 Prazic and Salaj et al found audiologically defined lesions in 36% of a group of 975 children treated with S sulfate for pulmonary TB.72 Hearing loss has also been reported in infants of tuberculous mothers treated with S during pregnancy.73 Familial occurrence of drug induced

Immunological and hematological adverse drug reactions

R has been associated with immune mediated thrombocytopenic purpura and haemolytic anaemia especially with intermittent dosing. In a Brazilian study, R induced thrombocytopenia, leukopenia, eosinophilia, hemolytic anemia, agranulocytosis, vasculitis, acute interstitial nephritis, and septic shock occurred in 0.1% of the patients.43,80 However, few Asian studies reported allergic reactions with FLDs' to be between 2.02% and 2.35% and hematological ADRs' to be 0.1–0.7%. Author in his work on

Arthralgia

Z and E are two anti-tuberculous drugs that have been reported to induce hyperuricemia in non-gouty patients leading to arthralgia.85 The metabolite pyrazinoic acid is likely responsible for the hyperuricemic effect. The mechanism is related to pyrazinoic acid, the principal metabolite of Z oxidized by xanthine oxidase, which inhibits the renal tubular secretion of uric acid.86 Hyperuricemia has been reported in 43–100% of patients treated with Z (alone or in combination).87 Gouty attacks have

Renal toxicity/nephrotoxicity

Aminoglycosides produce renal toxic effects due to their accumulation in the renal tubules. Such effects are more common in elderly individuals and in patients with a history of kidney disease. Prolonged use of aminoglycosides, hepatotoxicity, dehydration, hypotension and concurrent use of nephrotoxic drugs are other risk factors for renal toxicity. The risk of nephrotoxicity is less and range around 2% while using S.92,93 Injectable drugs such as Km and Am as well as Cm are more nephrotoxic as

Cutaneous adverse drug reactions (CADRS)

Z has been described to cause various skin reactions like maculopapular rash, erythema multiforme, exfoliative dermatitis, and drug, rash and eosinophilia with systemic symptoms (DRESS) syndrome. Among the FLDs', Z is the commonest cause of CADRS (2.38%), followed by S (1.45%), E (1.44%), R (1.23%), and Z (0.98%).95 It is not uncommon for exfoliative dermatitis to occur with more than one of the four drugs. It is unclear whether renal failure predisposes to increased occurrence of CADRS. So

Cardiotoxicity (QTc prolongation)

QTc prolongation on electrocardiogram (ECG) has been reported with FQs' particularly moxifloxacin (Mfx), macrolides such as Clarithromycin (Clr), Cfz, Bdq and Dlm.100,101 Risk factors for QTc prolongation include elderly, female sex, underlying cardiac disorder including congenital and acquired, electrolyte imbalance and concurrent use of ancillary medications. A systematic search showed that Bdq is a relatively well-tolerated drug, as its discontinuation occurred in only 3.4% and 0.6% of

Other adverse drug reactions

Few case reports on H induced gynecomastia among patients treated with anti-tubercular therapy.101,102 A rare occurrence of anaphylactic shock due to S was also reported.103

Management of adverse drug reactions

Management of ADRs' associated with anti-tubercular drugs is considered to be an essential component in order to achieve adequate adherence leading to favourable outcome. DR-TB patients with SLDs' requires special care as these drugs are more toxic. Principles of pharmacovigilance have been adopted by national TB control programmes all over the world. Pharmacovigilance is defined by the WHO as the “science and activities relating to the detection, assessment and prevention of ADRs or any other

Conclusion

The treatment of TB can cause a variety of ADRs'. ADRs' of varying severity are common during treatment of DS-TB and DR-TB, particularly in the intensive phase of therapy. Some ADRs' become more prevalent in DR-TB patients co-infected with HIV. Most ADRs' can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe ADRs' in the management of DR-TB patients are justified, however, they should not cause

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