Trial recommends new antibiotic for typhoid in low-income countries

Typhoid - also known as enteric fever - is characterised by a high fever and diarrhoea. It is transmitted through the ingestion of food or drink contaminated by the faeces or urine of infected people. It causes an estimated 26 million infections and more than 200,000 deaths each year, and the number of cases is particularly high in parts of South Asia.

The standard treatment for enteric fever since the 1950s has been the drug chloramphenicol. The spread of multi-drug-resistant forms of the Salmonella typhi and Salmonella paratyphi bacteria, which cause the disease, saw a move towards a new generation of antibiotics known as fluoroquinolones, but now there is evidence that the bacteria are becoming resistant to these drugs.

Gatifloxacin - a new type of fluoroquinolone - was released in North America in 1999 under the brand name Tequin by the pharmaceutical company Bristol-Myers Squibb. It was subsequently withdrawn following the 2006 publication of a retrospective Canadian study in the 'New England Journal of Medicine', which claimed that the drug can cause serious side-effects, including very high and low blood sugars.

In a study published last week, researchers from the Wellcome Trust Major Overseas Programme at the Oxford University Clinical Research Unit (Ho Chi Minh City, Vietnam), together with researchers at the Oxford University Clinical Research Unit-Patan Academy of Health Sciences (Kathmandu, Nepal), conducted an open-label, randomised, controlled trial to compare gatifloxacin to chloramphenicol. Their study, which enrolled 844 children and adults, is the largest randomised controlled trial for enteric fever carried out to date.

The researchers found both drugs to be equally effective and found no difference between the two drugs in terms of treatment failure and the time taken to clear the fever. However, the side-effects - including anorexia, nausea, diarrhoea and dizziness - were significantly worse in patients being treated with chloramphenicol.

An added advantage of gatifloxacin over chloramphenicol is that the former only needs to be take once a day for seven days, and the average cost for this treatment course is US$1.50. Chloramphenicol, by contrast, needs to be taken four times a day for 14 days, at an average price for the course of US$7. Gatifloxacin seems to work despite drug resistance to the older antibiotics (chloramphenicol and older fluoroquinolones) and therefore can be used in settings where the pattern of resistance is not known.

Because of concerns about the side-effects of gatifloxacin in an elderly North American population, the researchers closely monitored the patients' blood sugar levels. Although they found a higher number of patients with elevated blood sugar levels during the first week of treatment, these levels had returned to normal once the treatment course had ended and no change in treatment was required.

"Although there have been concerns of the side-effects of gatifloxacin in elderly people from North America, this was amongst a very different population to those needing the drug in the developing world," says Dr Buddha Basnyat.

"Gatifloxacin remains a very effective drug in young people who are not overweight and who have no tendency to diabetes. We have very few antibiotics for diseases of the developing world and it is very important that we do not lose the effective ones we have because of adverse events in a different population that we do not see in the population we treat."

The researchers have now submitted evidence to the World Health Organization (WHO) arguing that gatifloxacin should be retained in young populations not at risk of diabetes. It is understood that the WHO will consider this evidence later this year. The drug is also in phase III trials for the treatment of tuberculosis.