Drug-Resistant Tuberculosis Transmission and Resistance Amplification within Families

James A. Seddon

, Rob M. Warren, Donald A. Enarson, Nulda Beyers, and H. Simon Schaaf

Author affiliations: London School of Hygiene and Tropical Medicine, London, UK (J.A. Seddon); Stellenbosch University, Tygerberg, South Africa (J.A. Seddon, R.M. Warren, N. Beyers, H.S. Schaaf); International Union Against Tuberculosis and Lung Disease, Paris, France (D.A, Enarson); and Tygerberg Children’s Hospital, Tygerberg (H.S. Schaaf)

Abstract

Drug-resistant tuberculosis is caused by transmission of resistant strains of Mycobacterium tuberculosis and by acquisition of resistance through inadequate treatment. We investigated the clinical and molecular features of the disease in 2 families after drug-resistant tuberculosis was identified in 2 children. The findings demonstrate the potential for resistance to be transmitted and amplified within families.

The devastating effects of extensively drug-resistant tuberculosis (XDR TB) gained international attention after the 2006 outbreak in Tugela Ferry, South Africa. The evolution of the epidemic is the result of transmission of resistant strains and strain acquisition of resistance through inadequate treatment (1). Multidrug-resistant (MDR) TB is disease caused by Mycobacterium tuberculosis that is resistant to isoniazid and rifampin, and XDR TB is disease caused by M. tuberculosis that is additionally resistant to a fluoroquinolone and an injectable second-line anti-TB drug. Because children usually have transmitted resistance (2), they can be seen as the end of a sequence of transmission events. We describe investigations of 2 families after the identification of children with drug-resistant TB in terms of clinical features and molecular characteristics of the isolates.

The Study

This investigation was conducted in a suburban community of Cape Town, South Africa, where TB incidence was 978/100,000 population in 2009 (Health Systems Trust). Since 1994, microbiological samples from all patients treated for TB in this area have been sent to the research laboratory at Tygerberg Hospital, Stellenbosch University. From 2008 through 2010, two children from this community received a diagnosis of MDR TB.
Information was obtained from several sources to document the sequence of events that culminated in the development of MDR TB in each child. A home visit was made, and the family was interviewed after written informed consent was obtained. Family members were included if they either lived with or spent substantial amount of time with the child (3). Information on TB diagnosis, treatment, and outcome was obtained at interview. If a family member was identified as having had TB, family contacts of that person were included. Searches for case notes for those included were made at the local clinic, the academic hospitals, and the regional TB hospital responsible for drug-resistant TB management. Also, the local clinic TB register was consulted. The investigation was approved by the Stellenbosch University Ethics Committee.
Sputum samples from the 2 families were identified, and isolates were genotyped by spoligotyping (4) and IS6110 DNA fingerprinting (5). Strains were identified according to distinct IS6110 banding patterns by using Gelcompar II (Applied Maths, Sint-Martens-Latem, Belgium) or characteristic spoligotype pattern (6). Mutations conferring resistance to isoniazid, rifampin, ethambutol, pyrazinamide, ofloxacin, and amikacin were determined by DNA sequencing of the inhA promoter, katG, rpoB, embB, pncA, gyrA, and rrs genes, respectively (7).
A 19-month-old girl (A3) received a diagnosis of TB in March 2008 after a 6-month course of preventive therapy with isoniazid. She was brought for assessment with a 2-weeek history of cough, respiratory distress, and fever. She had contact with a patient with pre–XDR TB (MDR TB resistant to either a fluoroquinolone or a second-line injectable drug), and therefore the following antimicrobial drugs were administered: capreomycin, ethionamide, ethambutol, para-aminosalicylic acid, terizidone, clarithromycin, and high-dose isoniazid. Gastric aspirate samples were sent to the National Health Laboratory Service; M. tuberculosis grew in culture and was resistant to rifampin, isoniazid, and ofloxacin and susceptible to amikacin and ethionamide. She received treatment for 18 months from the time of her first negative culture (the first 6 months included the injectable medication) and recovered.