Skip to main content

Advertisement

SpringerLink
Log in

Diagnosis and Management of Multidrug-Resistant Tuberculosis in Children: A Practical Approach

  • Review Article
  • Published:
The Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Approximately 25,000 children develop multidrug-resistant (MDR) tuberculosis (TB) each year, but few of them are diagnosed and appropriately treated for MDR-TB. New diagnostic tools have improved our ability to diagnose children with bacteriologically confirmed TB earlier. However, the majority of childhood TB cases are not bacteriologically confirmed; therefore a high index of suspicion is needed, and taking a detailed history of contact with drug-resistant source cases and previous TB treatment is important to identify presumed MDR-TB cases. Treatment for MDR-TB is rapidly changing with the addition of new and repurposed drugs, the introduction of shorter regimens and the move towards injectable-free, all-oral MDR-TB treatment regimens. Children have been neglected in the introduction of the new drugs, but drug dosing and safety studies are now being completed. This article presents a practical approach in deciding which regimen to use in individual children in need of MDR-TB treatment. Outcomes in those treated are generally good, but only <5% of children with MDR-TB are currently diagnosed and appropriately treated. Diagnosing children with MDR-TB and getting them on to correct treatment regimens should now be our main focus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. World Health Organization, Geneva, Switzerland. Global Tuberculosis Report 2017. Available at: http://apps.who.int/iris/bitstream/10665/259366/1/9789241565516-eng.pdf?ua=1. Accessed 5 October 2018.

  2. Dodd PJ, Sismanidis C, Seddon JA. Global burden of drug-resistant tuberculosis in children: a mathematical modelling study. Lancet Infect Dis. 2016;16:1193–201.

    Article  PubMed  Google Scholar 

  3. Schaaf HS, Marais BJ, Hesseling AC, Brittle W, Donald PR. Surveillance of antituberculosis drug resistance amongst children from the Western Cape Province of South Africa – an upward trend. Am J Public Health. 2009;99:1486–90.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schaaf HS, Gie RP, Beyers N, Sirgel FA, de Klerk PJ, Donald PR. Primary drug-resistant tuberculosis in children. Int J Tuberc Lung Dis. 2000;4:1149–55.

    CAS  PubMed  Google Scholar 

  5. Seddon JA, Furin JJ, Gale M, Del Castillo Barrientos H, et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med. 2012;186:953–64.

    Article  CAS  PubMed  Google Scholar 

  6. Parr JB, Mitnick CD, Atwood SS, Chalco K, Bayona J, Becerra MC. Concordance of resistance profiles in households of patients with multidrug-resistant tuberculosis. Clin Infect Dis. 2014;58:392–5.

    Article  CAS  PubMed  Google Scholar 

  7. Shah NS, Yuen CM, Heo M, Tolman AW, Becerra MC. Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis. 2014;58:381–91.

    Article  PubMed  Google Scholar 

  8. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug resistant tuberculosis. Pediatr Infect Dis J. 2000;19:695–9.

    Article  CAS  PubMed  Google Scholar 

  9. Seddon JA. Time to be a bit more ‘surgical’ in our management of children with drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2015;19:625.

    Article  PubMed  Google Scholar 

  10. Schaaf HS, Garcia-Prats AJ, McKenna L, Seddon JA. Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children. Expert Rev Clin Pharmacol. 2018;11:233–44.

    Article  CAS  PubMed  Google Scholar 

  11. Raizada N, Sachdeva KS, Nair SA, et al. Enhancing TB case detection: experience in offering upfront Xpert MTB/RIF testing to pediatric presumptive TB and DR TB cases for early rapid diagnosis of drug sensitive and drug resistant TB. PLoS One. 2014;9:e105346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schaaf HS, Garcia-Prats AJ. Multidrug-resistant tuberculosis in children: recent developments in diagnosis, treatment and prevention. Curr Pediatr Rep. 2016;4:53–62.

    Article  Google Scholar 

  13. Tagliani E, Cabibbe AM, Miotto P, et al. Diagnostic performance of the new version (v2.0) of GenoType MTBDRsl assay for detection of resistance to fluoroquinolones and second-line injectable drugs: a multicenter study. J Clin Microbiol. 2015;53:2961–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Allix- Béguec C, Arandjelovic I, Bi L, et al. CRyPTIC Consortium and the 100,000 Genomes Project. Prediction of susceptibility to first-line tuberculosis drugs by DNA sequencing. N Engl J Med. 2018;379:1403–15.

    Article  PubMed  Google Scholar 

  15. Outhred AC, Jelfs P, Suliman B, et al. Added value of whole genome sequencing for management of highly drug-resistant TB. J Antimicrob Chemother. 2015;70:1198–202.

    CAS  PubMed  Google Scholar 

  16. Du Preez K, Schaaf HS, Dunbar R, et al. Complementary surveillance strategies are needed to better characterise the epidemiology, are pathways and treatment outcomes of tuberculosis in children. BMC Public Health. 2018;18:397.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wiseman CA, Gie RP, Starke JR, et al. A proposed comprehensive classification of tuberculosis disease severity in children. Pediatr Infect Dis J. 2012;31:347–52.

    Article  PubMed  Google Scholar 

  18. Seddon JA, Hesseling AC, Godfrey-Faussett P, Schaaf HS. High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study. Thorax. 2014;69:458–64.

    Article  PubMed  Google Scholar 

  19. Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous system tuberculosis. Indian J Radiol Imaging. 2009;19:256–65.

    Article  PubMed  PubMed Central  Google Scholar 

  20. World Health Organization, Geneva, Switzerland. WHO treatment guidelines for drug-resistant tuberculosis 2016 update WHO/HTM/TB/201604 Available at: http://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-eng.pdf?sequence=1. Accessed 11 June 2018.

  21. Seddon JA, Schaaf HS, Marais BJ, et al. Time to act on injectable-free regimens for children with multidrug-resistant tuberculosis. Lancet Respir Med. 2018;6:662–4.

    Article  PubMed  Google Scholar 

  22. World Health Organization. Rapid communication: key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). WHO/CDS/TB/2018.18.Available at: www.who.int/tb/publications/2018/rapid_communications_MDR/en/. Accessed 1 Oct 2018.

  23. Weyer K, Falzon D, Jaramillo E. Towards all-oral and shorter treatment regimens for drug-resistant tuberculosis. Bull World Health Organ. 2018;96:667–667A.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Schaaf HS, Thee S, van der Laan L, Hesseling AC, Garcia-Prats AJ. Adverse effects of second-line antituberculosis drugs in children. Expert Opin Drug Saf. 2016;15:1369–81.

    Article  CAS  PubMed  Google Scholar 

  25. Garcia-Prats AJ, Rose PC, Draper HR, et al. Effect of co-administration of lidocaine on the pain and pharmacokinetics of intramuscular amikacin in children with multidrug-resistant tuberculosis: a randomized crossover trial. Pediatr Infect Dis J. Published ahead of print, 14 Mar 2018. https://doi.org/10.1097/INF.0000000000001983 PMID: 29561515.

  26. DR-TB STAT. Phase III Clinical trial results at the 48th union world conference on lung health: implications for the field.Available at: https://www.ghdonline.org/uploads/Updated_November_12_2017_STAT_phaseIII_Union_summary.pdf.Accessed 6 Oct 2018.

  27. Selvakumar N, Kumar V, Balaji S, et al. High rates of ofloxacin resistance in Mycobacterium tuberculosis among both new and previously treated patients in Tamil Nadu. South India. PLoS One. 2015;10:e0117421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Statement on injectable-free regimens for children under the age of 12 years with rifampicin-resistant Tuberculosis. Available at: http://sentinel-project.org/wp-content/uploads/2018/07/Recommendations-for-Injectible-Free-Regimens-in-Children-with-Rif-Resistant-TB.pdf. Accessed 4 Oct 2018.

  29. Seddon JA, Thee S, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in children treated for multidrug-resistant tuberculosis. J Inf Secur. 2013;66:320–9.

    Google Scholar 

  30. Zhao Y, Fox T, Manning K, et al. Improved treatment outcomes with bedaquiline when substituted for second-line injectable agents in multidrug-resistant tuberculosis: a retrospective cohort study. Clin Infect Dis. 2018 Aug 24. https://doi.org/10.1093/cid/ciy727.

  31. Brill MJ, Svensson EM, Pandie M, et al. Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis. Int J Antimicrob Agents. 2017;49:212–7.

    Article  CAS  PubMed  Google Scholar 

  32. Mallikaarjun S, Wells C, Petersen C, et al. Delamanid coadministered with antiretroviral drugs or antituberculosis drugs shows no clinically relevant drug-drug interactions in healthy subjects. Antimicrob Agents Chemother. 2016;60:5976–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J. 2012;40:1277–86.

    Article  PubMed  Google Scholar 

  34. Osman M, Harausz EP, Garcia-Prats AJ, et al. For the collaborative Group for Meta-Analysis of Paediatric individual patient data in MDR-TB. Encouraging treatment outcomes among children with extensively drug-resistant tuberculosis: a global systematic review and individual patient meta-analysis. Emerg Infect Dis. 2018; in press.

  35. Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12:449–56.

    Article  PubMed  Google Scholar 

  36. Harausz EP, Garcia-Prats AJ, Law S, et al. Collaborative Group for Meta-Analysis of Paediatric individual patient data in MDR-TB. Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis. PLoS Med. 2018;15:e1002591.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis in children. Int J Tuberc Lung Dis. 2018;22:3–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dodd PJ, Yuen CM, Sismanidis C, Seddon JA, Jenkins HE. The global burden of tuberculosis mortality in children: a mathematical modelling study. Lancet Glob Health. 2017;5:e898–906.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Svensson EM, du Bois J, Kitshoff R, et al. Relative bioavailability of bedaquiline tablets suspended in water: implications for dosing in children. Br J Clin Pharmacol. 2018;84:2384–92.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgement

The author acknowledges the help of Dr. Anthony J. Garcia–Prats for critically reviewing the manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa

    H. Simon Schaaf

Authors
  1. H. Simon Schaaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Simon Schaaf.

Ethics declarations

Conflict of Interest

HS Schaaf is co-investigator on a dose-finding and safety trial of Delamanid in children for which Stellenbosch University receives a per patient grant from Otsuka.

Source of Funding

HS Schaaf received financial support from the National Research Foundation (South Africa) for his research.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schaaf, H. Diagnosis and Management of Multidrug-Resistant Tuberculosis in Children: A Practical Approach. Indian J Pediatr 86, 717–724 (2019). https://doi.org/10.1007/s12098-018-02846-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12098-018-02846-8

Keywords

Search

Navigation