Elsevier

Tuberculosis

Volume 92, Issue 1, January 2012, Pages 9-17
Tuberculosis

Review
Paediatric use of second-line anti-tuberculosis agents: A review

https://doi.org/10.1016/j.tube.2011.11.001Get rights and content

Summary

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.

Introduction

It is rarely emphasized that multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) also affect children and that paediatric drug-resistant TB can be viewed as an emerging global epidemic.1 MDR-TB is defined as Mycobacterium tuberculosis (M. tuberculosis) resistant to the most potent first-line anti-TB medications, isoniazid and rifampicin, while XDR-TB has additional resistance to the most active second-line agents, injectable drugs (aminoglycosides and/or cyclic polypeptides) and fluoroquinolones. There were an estimated 440,000 cases globally of MDR-TB during 2009.2 Given the fact that childhood TB represents at least 10–20% of the total cases in areas with poor epidemic control,3, 4, 5 this translates into a minimum global estimate of around 40,000 paediatric cases of MDR-TB per year. Accurate reporting and optimal management of these cases are challenging, due to the difficulty in confirming the diagnosis, limited awareness and experience in dealing with these patients, the complexity and duration of treatment, and the limited availability of adequate drugs and child-friendly formulations. In addition, in settings with a high burden of MDR-TB and human immunodeficiency virus (HIV), up to 40% of children with MDR-TB are also HIV-infected.6 These children are at risk of multiple opportunistic infections, have specific nutritional and metabolic requirements and absorb medications in a different manner to those HIV-uninfected. The combination of MDR-TB and HIV can have serious psychological effects. Both conditions are stigmatised and are perceived to carry poor prognosis. HIV-infected children are also treated with antiretroviral therapy (ART) medications which have the potential to interact with the second-line anti-TB drugs. Few studies have examined the management of children with MDR-TB. Those that have are small and focus mainly on outcomes with little attention to the careful documentation of the challenges of treatment.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 With the imminent roll-out of more rapid, molecular diagnostic tests to identify MDR-TB,20, 21 case detection, including that of children, is likely to rise. In order to manage children with MDR-TB it is important to understand the currently available medications, their indications, dosages, pharmacokinetic properties and their potential adverse effects. This article discusses the available second-line anti-TB drugs in respect to paediatric usage. We also review the potential interaction between second-line drugs and the ART medications.

Section snippets

Treatment of MDR-TB in children: general considerations

Children are typically diagnosed with either confirmed or presumed MDR-TB. Confirmed disease occurs when an organism is isolated from the child and is shown to be either genotypically or phenotypically resistant to isoniazid and rifampicin. Presumed disease occurs when TB is diagnosed in combination with either known contact with an MDR-TB source case or after the failure of appropriate first-line therapy where adherence has been verified. When confirmed, the treatment should be tailored to the

Characteristics of the second-line drugs in children

The available TB drugs used in the treatment of MDR-TB are placed in five groups, summarized in Table 1.36 When designing a regimen to treat children with MDR-TB, the World Health Organisation (WHO) suggests initially using any first-line drugs to which the organism is still susceptible. An injectable drug should be added from group two, a fluoroquinolone from group three and then further agents from groups four and five to make up a regimen containing at least four, preferably five drugs, to

Safety and toxicity

Monitoring and describing adverse effects (Table 2) in children is challenging; young children cannot articulate pain, nausea, vertigo, peripheral neuropathy, anxiety or confusion. Rashes are common due to a variety of aetiologies and the testing of hearing and vision is more difficult than in adults. However, it is particularly important to detect adverse effects as, in addition to life-threatening and unpleasant effects, growth and neuro-cognitive development may be affected. Children treated

Effect of HIV co-infection and interaction with ART

Co-infection with both TB and HIV is common in areas where both diseases are widespread.190, 191 Rapid initiation of ART in children with MDR-TB is critical due to the advanced spectrum of TB disease and high mortality observed in this paediatric subpopulation.6 The drug interactions between ART and first-line TB drugs have been extensively reviewed.192, 193 Rifampicin reduces the concentrations of many concomitantly administered drugs including the key antiretroviral non-nucleoside reverse

Conclusions

The management of paediatric MDR-TB is challenging, largely due to the complicated and toxic drugs currently used. It is vital that clinicians managing such children are familiar with the available drugs. Given the scale of the challenge it is concerning that so little primary data are available to inform practitioners. Traditionally the treatment of children with TB was not regarded to be a public health priority and cases were under-reported due to the challenges in establishing a definitive

Financial support

This work was supported by a grant (GHN-A-00-08-00004-00) from TREAT TB, USAID (JAS and HSS), the Sir Halley Steward Trust (JAS), the South African Medical Research Council (HSS) and the National Research Foundation of South Africa (HSS and PRD). HM received partial support from SATBAT through the Fogarty International Center (U2RTW007370/3, 5U2RTW007373).

Competing interests

None declared.

Funding

The funding agencies had no role in the design or conduct of the study, in the collection, management, analysis or interpretation of the data, or in the preparation, review, or approval of the manuscript.

Ethical approval

Not required.

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