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SAMJ: South African Medical Journal

On-line version ISSN 2078-5135
Print version ISSN 0256-9574

SAMJ, S. Afr. med. j. vol.105 n.5 Pretoria May. 2015 



Paediatric chemoprophylaxis for child contacts of patients with drug-resistant tuberculosis: Are current guidelines effective in preventing disease?



To the Editor: The World Health Organization (WHO) estimates that there were 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB) in 2013.[1] Alarmingly, 40% of MDR-TB cases for which second-line drug susceptibility test results were reported originated in South Africa (SA).[1] This has important implications in vulnerable populations, such as children, where infection with drug-resistant strains of TB are usually attributable to transmission rather than acquisition of resistance.[2] In high-burden settings, it is estimated that there are at least two child contacts who are either HIV-infected or younger than 5 years of age for every MDR-TB source case.[3,4] The growing spread of MDR-TB, the protracted and toxic nature of current treatment regimens and the associated morbidity and mortality all emphasise the need for effective preventive therapy. There is limited evidence on optimal paediatric chemoprophylaxis to prevent disease in child contacts of MDR-TB cases, and the subject remains controversial. We have examined recently adapted paediatric chemoprophylactic guidelines and evaluated their effectiveness in the context of drug-resistant TB. We highlight a critical gap in research that is urgently needed to guide policy.

The 2013 South African Guidelines for the Management of Tuberculosis in Children make the following recommendations, following exclusion of TB disease: (i) isoniazid preventive therapy (IPT; 10 - 15 mg/kg/day for 6 months) in all child contacts that are HIV infected or <5 years of age; (ii) rifampicin (15 mg/kg/day for 4 months) in isoniazid mono-resistant index cases; and (iii) high-dose isoniazid (15 - 20 mg/kg for 6 months) for neonates born to mothers with infectious drug-resistant TB.[5] While IPT significantly reduces the risk of drug-susceptible TB disease, and possibly TB strains with low-level isoniazid resistance, its applicability in the prevention of MDR-TB disease is questionable. Indeed, Kritski et al.[6] found that isoniazid had no protective effect in adult and child contacts of MDR-TB patients. In addition, Sneag et al.[7] described the failure of chemoprophylaxis with standard antituberculosis agents in five child contacts of MDR-TB patients.

There are no randomised chemoprophylaxis clinical trials for child contacts of MDR-TB patients. A prospective study in the Federal States of Micronesia found that of 110 adult and child MDR-TB contacts, administered a tailored (based on the susceptibility pattern of the source case) 12-month, multidrug prophylactic regimen, none developed TB disease.[8] Two studies conducted in SA report similar findings. Schaaf et al. [3]prospectively followed up 105 child contacts of adult MDR-TB patients for 30 months. Only 5% (2/41) of children who received an individualised, multidrug prophylactic regimen developed TB disease compared with 20% (13/64) of children who were monitored without preventive therapy. Most recently, Seddon et al.[9] demonstrated that a three-drug prophylactic regimen consisting of high-dose isoniazid, ofloxacin and ethambutol for 6 months was both effective and well tolerated in child contacts of MDR-TB; only 3.2% of children (6/186) developed incident TB.

Although there is a growing number of observational studies suggesting that MDR-TB chemoprophylaxis may be beneficial in MDR-TB-exposed children, there is still a lack of international consensus on the management of child contacts of MDR-TB patients. The WHO does not advocate the use of second-line agents as chemoprophylaxis for contacts of MDR-TB patients.[5] Likewise, the UK National Institute for Health and Clinical Excellence recommends close follow-up rather than intervention.[4] In contrast, several US institutions support the use of a regimen containing two drugs to which the source case is susceptible.[4] Such discordance is largely attributable to the potential adverse effects associated with anti-MDR-TB drugs. Both Bamrah et al.[8] and Seddon et al.[9] have reported good drug tolerability, however, with only 0 - 5.5% of patients experiencing adverse effects necessitating treatment interruption.

The lifetime risk of progression to active TB disease is 5 - 15% in people with latent infection.[10] Given that this figure rises sharply to 50% in children younger than 12 months,[11] and that inadequate chemotherapy may result in significant morbidity, the management of children with latent TB (including MDR-TB) is fundamental to TB control. In the absence of a randomised clinical trial, observational studies strongly indicate that appropriate MDR-TB chemoprophylaxis should be considered when TB disease has been excluded, there is significant exposure to a close drug-resistant TB contact and the risk of disease progression is high. More research is urgently required to conclusively guide policy.

Acknowledgments. NP and NN are supported by the Centre for the AIDS Programme of Research in South Africa (CAPRISA). Research reported in this publication was supported by the South African Medical Research Council.

Nesri Padayatchi, Naressa Naidu
South African Medical Research Council (SAMRC)/Centre for the AIDS Programme of Research in South Africa (CAPRISA) HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa



1. World Health Organization. Global Tuberculosis Report 2014. Geneva: World Health Organization, 2014. (accessed 16 February 2015).         [ Links ]

2. Seddon JA, Hesseling AC, Marais BJ, Jordaan A, Victor T, Schaaf HS. The evolving epidemic of drug-resistant tuberculosis among children in Cape Town, South Africa. Int J Tuberc Lung Dis 2012;16(7):928-933. []        [ Links ]

3. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: A 30-month follow-up. Pediatrics 2002;109(5):765-771. []        [ Links ]

4. Seddon JA, Godfrey-Faussett P, Hesseling AC, Gie RP, Beyers N, Schaaf HS. Management of children exposed to multidrug-resistant Mycobacterium tuberculosis. Lancet Infect Dis 2012;12(6):469-479. []        [ Links ]

5. Department of Health South Africa. Guidelines for the Managment of Tuberculosis in Children. South Africa: National Department of Health, 2013. (accessed 16 February 2015).         [ Links ]

6. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 1996;153(1):331-335. []        [ Links ]

7. Sneag DB, Schaaf HS, Cotton MF, Zar HJ. Failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases. Pediatr Infect Dis J 2007;26(12):1142-1146. []        [ Links ]

8. Bamrah S, Brostrom R, Setlik L, Fred D, Kawamura M, Mase S. An ounce of prevention: Treating MDR-TB contacts in a resource limited setting. Presented at the International Union of Tuberculosis and Lung Disease Conference, 11-15 November 2010, Berlin, Germany.         [ Links ]

9. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: A prospective cohort study. Clin Infect Dis 2013;57(12):1676-1684. []        [ Links ]

10. Mandell GL, Bennet JL, Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000.         [ Links ]

11. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: A critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8(4):392-402.         [ Links ]

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