Significant increase in isoniazid-resistant TB in UK

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Resistance to isoniazid, a key anti-tuberculosis (TB) drug in England, Wales and Northern Ireland, has increased significantly in recent years, according to study published in the British Medical Journal on May 2nd.

This increase was particularly notable in London, and likely reasons include migration and “inadequate control of transmission” in the capital. There has been a slight increase in the number of TB cases that are multidrug resistant (MDR), but only one case of extensively drug resistant has been seen. The investigators think that most cases of MDR-TB seen in the UK are due to poor patient adherence to therapy rather than transmission between individuals.

Since 1987 the number of TB cases seen in England, Wales and Northern Ireland has increased significantly, with more than 8,000 cases reported in 2006. Resistance to TB drugs is increasing around the world, and there has been some evidence of transmission of drug-resistant strains of TB between drug users and prisoners in London.

Glossary

isoniazid

An antibiotic that works by stopping the growth of bacteria. It is used with other medications to treat active tuberculosis (TB) infections, and on its own to prevent active TB in people who may be infected with the bacteria without showing any symptoms (latent TB). 

multidrug-resistant tuberculosis (MDR-TB)

A specific form of drug-resistant TB, due to bacilli resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. MDR-TB usually occurs when treatment is interrupted, thus allowing organisms in which mutations for drug resistance have occurred to proliferate.

not significant

Usually means ‘not statistically significant’, meaning that the observed difference between two or more figures could have arisen by chance. 

extensively drug-resistant TB (XDR-TB)

A form of drug-resistant tuberculosis in which bacteria are resistant to isoniazid and rifampicin, the two most powerful anti-TB drugs, plus any fluoroquinolone and at least one injectable second-line drug. 

first-line therapy

The regimen used when starting treatment for the first time.

Investigators from the UK’s Health Protection Agency therefore looked at trends in resistance to anti-TB drugs in England, Wales and Northern Ireland between 1998 and 2005.

Results from 28,620 culture-confirmed TB cases were available for analysis. The patients from whom these samples were collected had a median age of 35, 57% were male, 69% were born outside the UK, 24% had entered the UK within the last two years, and 42% of the cases were within London.

The percentage of TB cases with resistance to any of the drugs used in first-line treatment increased from 5.6% in 1998 to 7.5% in 2005. The investigators then looked at the trends for individual drugs. They found that resistance to isoniazid increased from 5% to 7.2% in 2003 and remained stable thereafter. There was a slight increase in resistance to rifampicin from 1% to 1.2% and a modest increase in the proportion of TB cases that were multidrug resistant (0.8% to 0.9%).

Detailed statistical analysis showed that the increase in isoniazid resistance outside London was not significant. The increase in multidrug resistant TB was also statistically insignificant after the investigators controlled for previous TB diagnosis and treatment. However, in London the rise in isoniazid resistance was statistically significant.

Younger age was a risk factors for any resistance to TB drugs. In London, the risk of isoniazid was higher for black Caribbean patients than for white patients. Outside London, black African, Indian, Pakistani, Bangladeshi and Chinese origin were associated with both multidrug resistance and rifampicin resistance.

There was little evidence of resistance to second- and third-line anti-TB drugs, and only one case of XDR-TB was seen (in 2003) in a patient with no previous history of TB.

Six clusters of MDR-TB were identified and these involved just under 20% of all MDR-TB cases. One cluster involved six patients, five of whom lived in the same area and was classified as an “outbreak.” All the patients were from an ethnic minority and were born both within and outside the UK. Four MDR-TB cases were part of an outbreak of isoniazid resistance in London, with resistance to rifampicin developing as a result of poor adherence. A cluster of three or four cases is “less likely” to have originated in the UK as two of the patients arrived in the UK from Asia within the previous five years. The remaining three clusters each involved two patients and involved household transmission.

The investigators comment, “the increase in isoniazid resistance is probably related to increasing numbers of patients with drug resistant tuberculosis from sub-Saharan Africa and the Indian sub-continent. The increase in cases from these parts of the world reflects, at least in part, a general change in the UK population resulting from ongoing migration.”

However, increases in isoniazid resistance in London cannot, the investigators write, be attributed to migration, but rather reflects “a major outbreak of isoniazid resistance…the outbreak is associated with imprisonment and drug misuse. More than 300 cases have been identified to date as part of this outbreak, mainly in north London.” They note that the outbreak is still continuing, “suggesting that control measures are insufficient.”

The investigators believe that the small number of cases with resistance to second- and third-line TB drugs suggests “that such patients are being managed effectively, preventing the emergence of further resistance.”

A limitation of the study was that the investigators were not able to determine the HIV status of patients.

The investigators conclude “transmission of multidrug resistant tuberculosis within the UK is limited. Cases that arise de novo…suggest that failures in the management of patients in the UK are contributing to the occurrence of multidrug resistance.”

References

Kruijshaar ME et al. Increasing antituberculosis drug resistance in the United Kingdom: analysis of national surveillance data. British Medical Journal (online first), 2008.

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