15 May 2015
The dangers of antimicrobial resistance (AMR) were back in the news this week, including more alarming headlines about the rise of so-called superbugs, and a call to arms to the pharmaceutical industry to lead the way on the development of new antibiotics.
The latest report from the UK Review on Antimicrobial Resistance outlines what needs to be done to boost the development of new antibiotics. Measures include setting up a global innovation fund for drug development and a financial reward system for those companies that are successful. While measures such as these, if implemented, could have an impact, the authors of the review point out that this is only one of many challenges associated with tackling AMR.
AMR: understanding the problem
One of the most pressing of these challenges to fully understand the scale of the problem of AMR, which is not clear for some common diseases, particularly those that are endemic in developing countries. One such disease is typhoid, the subject of paper published in Nature Genetics this week that has characterised the spread of multi-drug resistant (MDR) typhoid, outlining more evidence that the problem of AMR in this disease is growing.
Typhoid is caused by a sub-type of the bacteria Salmonella (Full name: Salmonella enterica serovar Typhi, or S. typhi for short) and is spread by exposure to food or water contaminated with the faeces of an infected person. It is associated with poor sanitation and hygiene and affects approximately 21 million people per year, causing around 200,000 deaths. Symptoms include fever, abdominal pain and headaches. There is an effective vaccine and treatment with antibiotics significantly reduces the death rate to 1-2% of those infected, compared to 10-20% death rate without antibiotics.
There are three first-line drugs available however resistance started emerging to these drugs in the 1970s due to S. typhi acquiring plasmids – small circular sections of DNA that can be transmitted between bacteria – carrying mutations in genes that confer resistance. Alternative second-line drugs are available however some S. typhi also have mutations in their chromosomal DNA, which makes them resistant to one group of these drugs, the fluoroquinolones.
The authors of the Nature Genetics paper have characterised the location and spread of one type of multi-drug resistant (MDR) S. typhi, known as H58, that has the mutations described above. They show that H58 has emerged as the single dominant pathogen causing MDR typhoid and that it is becoming more common by displacing drug-susceptible forms of the bacteria.
Transmission between and within continents
The research team used whole genome sequencing to analyse 1,832 samples of S. typhi collected from locations world-wide between 1905 and 2013. In their samples, H58 first appeared in 1992, and in total 47% of their samples were the H58 type. By comparing the genome sequences of susceptible and resistant samples, the team were able to estimate transmission events between countries, and how often these might have occurred. Their data suggest that major transmission events of H58 occurred multiple times from the Indian sub-continent to south-east Asia, western Asia and Africa. Within Africa, transmission took place many times from eastern to southern Africa, and further within the continent. In Africa the spread of H58 S. typhi, particularly to areas where it wasn't previously common, suggests that an ongoing unrecognised epidemic of typhoid is occurring.
While multi-drug resistance is a common feature of H58, the genetic basis of that resistance reflects the antibiotic treatment strategies in the country where the sample was collected. For example, fluoroquinolone use is common in SE Asia and H58 samples from this region are more likely to contain mutations conferring resistance to these drugs. In Africa, the resistance genes found in the samples reflect the use of the traditional front-line treatments.
Finding the right management strategy
There are many challenges to be overcome in the management of typhoid, a disease that disproportionately affects developing countries. Patients can become chronic carriers of the pathogen, developing long-term systemic infections. Others carry the pathogen asymptomatically, and continue to transmit it unknowingly, and play a role in maintaining environmental reservoirs of the pathogen. Improved sanitation greatly reduces the transmission of typhoid, by preventing contamination of food and water sources. While there are many international efforts to improve access to clean water and sanitation, there is still much that needs to be done to improve access, particularly in rural areas.
The right drug in the right location
Vaccination is known to be effect ive against typhoid, so large-scale vaccination programmes will have an impact in affected areas. Additional public health measures such as long-term routine surveillance using whole genome sequencing to determine how H58 is spreading further and to find out its resistance type, can be used to inform effective antibiotic use and treatment choice according to what the pathogen is resistant to. However these measures, and the development of new drugs, will only go so far if people cannot access clean water and sanitation and significantly reduce the spread of the pathogen. For a disease such as typhoid, preventative measures will be just as important as the cure.