Drug resistant TB on rise in UK

“Cases of drug-resistant tuberculosis are on the rise”, the Daily Mail reported today. The Guardian also says that a study published in the British Medical Journal has found that cases of drug resistant TB in the UK nearly doubled between 1998 and 2005. They report that rising immigration and inadequate measures to control outbreaks “among prisoners and drug users” could be to blame. The Daily Mail also says the increase is thought to be linked to immigrants, particularly from sub-Saharan Africa and the Indian subcontinent, contracting drug-resistant TB abroad before moving to Britain.

Cases of TB have been occurring with increasing frequency over recent decades. As with other bacterial infections, drug resistant forms of TB will develop over time as bacteria adapt to overcome the actions of commonly used antibiotics. The increase in resistance to one first-line drug treatment for TB (isoniazid) has been small, but significant, since 1998. There are still treatment options for which resistance has not increased.

As the researchers behind this study point out, this highlights the need for early diagnosis of suspected cases, the rapid testing for the types of antibiotic to which the particular strain of TB is susceptible and ensuring that patients complete their course of treatment.

Where did the story come from?

Michelle E. Kruijshaar and colleagues from the Health Protection Agency and Queen Mary’s School of Medicine and Dentistry, London, Newcastle General Hospital, the Heart of England NHS Foundation Trust, Birmingham, and the University of East Anglia, carried out the research. The researchers received no funding for this study. The study was published in the peer-reviewed medical journal: British Medical Journal.

What kind of scientific study was this?

In this time-trend study, the researchers investigated trends in the UK for antibiotic resistance to tuberculosis (TB) between 1998 and 2005. The study also investigated possible causes for any changes in resistance.

The researchers wanted to include cases of TB that were reported between 1998 and 2005 and the antibiotics they had proved susceptible to. In order to do this, they combined data from two databases, the Mycobacterial Surveillance Network (MycobNet), which collects information about the drug susceptibility of circulating strains of TB, and the national enhanced tuberculosis surveillance database, which provided clinical information on the cases.

The cases in the databases were either confirmed by a laboratory culture or by a doctor’s diagnosis and decision to treat as TB based on clinical and radiological findings (non-culture confirmation). For this analysis, the researchers only included those cases confirmed by a culture.

The researchers examined trends in the resistance of TB to antituberculous drugs over the eight-year period. They saw how these were affected by individual variables such as age, sex, ethnicity, place of birth, region of habitation in the UK, previous diagnoses and site of disease (e.g. TB just affecting the lungs or with involvement of other parts of the body).

Multidrug resistance was defined as a case of TB that was resistant to two of the most commonly used drugs (isoniazid and rifampicin).

What were the results of the study?

Between 1998 and 2005, there were a total of 28,620 cases of TB in the UK confirmed by bacterial culture. The average age of TB patients in this period was 35 and 57% were male. Forty two per cent of the cases occurred in London and 69% of the patients had been born outside of the UK and of those, the average time that they had been in the UK before diagnosis was four years. There were 25,117 identified cases not confirmed by culture.

Results of drug susceptibility testing were available for nearly 100% of the culture-confirmed cases and this showed that the proportion of cases resistant to first line drugs rose from 5.6% in 1998 to 7.5% in 2005. Looking at the individual antibiotics separately, there were rises in resistance to isoniazid (5.0 to 6.9%) and rifampicin (1.0 to 1.2%), but not for two other drugs (ethambutol and pyrazinamide).

When the researchers looked at factors associated with the trends, they found there was a significant increase in isoniazid resistance within London over time. This was of borderline statistical significance (OR 1.04, 95% CI 1.00 to 1.07). There was no increase in isoniazid resistance over time outside of London. These measures were adjusted for ethnicity, place of birth and age. There were no significant increases in rifampicin or multidrug resistance when adjusted for other variables.

Those younger and born outside of the UK had a higher risk of drug resistance outside of London, but being born outside of the UK was linked with lower risk of isoniazid resistance within London. Those with a previous diagnosis were significantly more likely to be resistant to isoniazid. There were differences in risk of isoniazid resistance both within and outside of London between ethnic groups.

Resistance to other second and third line drug options was found to be low.

What interpretations did the researchers draw from these results?

The authors conclude that the proportion of cases of TB that were resistant to isoniazid increased from 1998 to 2005 and that this ‘reflects the increasing proportion of patients with tuberculosis who are not born in the UK and who are from certain ethnic minority groups, as well as inadequate control of transmission in London’.

They say this highlights the need for completing the recommended drug courses and instituting measures to control outbreaks in London.

What does the NHS Knowledge Service make of this study?

Cases of tuberculosis have been occurring with increasing frequency over recent decades and a higher proportion of cases occur in those who were born outside of the UK. However, as the authors say, it is “failures in management of patients in the UK [that] are contributing to the occurrence of multidrug resistance”.

As with other bacterial infections, the development of drug resistant forms of TB over time will invariably happen as antibiotics are used more regularly and bacteria adapt to overcome their actions. London is a large city with a high population density and is therefore going to take a large burden of these cases.

The method of data collection does have some limitations as the researchers acknowledge. For example:

• Drug-resistant TB may be particularly prevalent among people living in relative poverty, the homeless or illicit drug users with whom the surveillance databases may have failed to identify. This would mean that the prevalence of TB in urban areas such as London is even higher than that found by this study.
• The data does not account for other diseases or conditions that TB patients may have that could affect drug resistance, e.g. HIV.
• The researchers only included cases of TB that could be found in both databases. There could have been inaccuracies in the matching of the cases between the two databases.
• Cases of TB that had not been confirmed by a bacterial culture were not included in analyses. As there were a large number of these (25,117 cases), the patterns in this group could have swayed the overall findings, i.e. if resistance had not increased or had even reduced over time in this group, the overall result is unlikely to be significant considering how borderline the results are in the culture-confirmed cases.

There was less information on the use of second and third line drugs. However, the finding that resistance was low when they were used, suggests that cases can still be managed effectively. Similarly with rifampicin (another first line option for TB in the UK), there was no increase in resistance over time. This study highlights the need for early diagnosis of suspected cases, rapid testing for the types of antibiotic to which the tuberculosis strain is susceptible, and the importance of ensuring that patients complete their treatment courses. Continued surveillance is important in order to try prevent drug resistance from developing into the future.

Sir Muir Gray adds...

Very cunning little beasts bacteria, as soon as you let your standards slip and don’t treat them with respect, they mutate and attack even more viciously.