It looks like it’s time to pay the piper. The first extensively drug-resistant (XDR) strain of Salmonella typhimurium, called ST313 sublineage II.1, has cropped up in the Democratic Republic of Congo (DRC). This fails to respond to any of the antibiotics that are commonly used in the DRC, except for ciprofloxacin. And to make things worse, one sample has been isolated that shows incomplete response even to this last drug.
S. typhimurium, which many researchers say originated in sub-Saharan Africa some decades ago, has been showing increasingly broad resistance to antibiotics over the last decades. According to the new study which reports the emergence of this new strain of S. typhimurium in the journal Nature Communications on September 19, 2019, this is a threat which will need the close cooperation of microbiologists, geneticists, and epidemiologists, in addition to clinicians and other specialists, if it is to be identified and controlled in different locations.
Salmonella bacteria. S. typhi, S. typhimurium and other Salmonella, Gram-negative rod-shaped bacteria, 3D illustration - Illustration Credit: Kateryna Kon / Shutterstock
Salmonella is more commonly known to cause food poisoning, not necessarily life-threatening though very uncomfortable. However, things are different when it comes to S. typhimurium and related strains, which are better known to cause two-thirds of bloodstream infections in this region. In fact, these have gained their own name: invasive non-typhoidal Salmonella (iNTS) infections. Such infections affect almost 3.5 million people a year, and almost 700,000 thousand people meet their death this way – with the greatest danger coming from S. typhimurium. The worst thing is that iNTS infections are rife in the very places which have the lowest availability of healthcare, a poorly equipped system, and low levels of immunity. In these places, it is the children under 5 years of age who bear the brunt.
The exact strain of S. typhimurium producing iNTS in this region is typically ST313, which is known to be resistant to drugs. This has also given rise to two new variants called lineage I and lineage II, which have spread independently to cover most of Africa, fueled by two factors: HIV prevalence and multidrug resistance (MDR). Lineage II infections are now the main cause of iNTS.
What does XDR mean?
MDR pathogens are resistant to ampicillin, trimethoprim/sulfamethoxazole and chloramphenicol. This should not create a problem with iNTS, which is typically treated with the fluoroquinolone antibiotic ciprofloxacin. On the other hand, complicated iNTS requires ceftriaxone – but ST313 lineage II is now showing the presence of extended-spectrum beta-lactamase enzymes, which means they do not respond to newer cephalosporins either, like ceftriaxone. This fits the definition of XDR as applied to S. typhi, that is, resistant to five drugs.
Expanded, this means the bacteria show MDR along with resistance to the two second-line drugs, ceftriaxone (through extended-spectrum beta-lactamase enzymes), and azithromycin. This leaves only the fluoroquinolones. However, one sample has already been isolated which is not susceptible to this either – a pan-resistant pathogen. This evolving strain, dubbed lineage II.1, is responsible for more than 10% of isolates in the central part of the DRC.
New invasive changes
The most worrying part is yet to come. Not only is the bacterium becoming increasingly resistant to all antibiotics, but it is shifting towards becoming a primary bloodstream pathogen. In the first case, researchers found that a single plasmid carried all the resistance genes. A plasmid is a package of genetic material that can be transferred from cell to cell. Moreover, the new lineage II strain is undergoing several changes, both in its genome and in its behavior, which means it is becoming more and more geared up for bloodstream infections – becoming “invasive”, in other words.
Invasive characteristics have been detected both in laboratory experiments as well as by the innovative use of machine learning algorithms. These techniques helped to pick up characteristic patterns in the DNA that indicate which strains are becoming invasive. These include less stimulation of the host immune system, lower metabolism, loss of one type of flagella and greater tendency to form biofilms.
Why did this happen?
It could be due to the excessive use of antibiotics, says the study. Azithromycin was recently used in a mass campaign to wipe out trachoma, an infectious cause of blindness, and also is extensively used in children. The plasmid found in lineage II strains has previously been found in other iNTS-associated S. typhimurium.
Over the past decade, all bloodstream infections have been put under surveillance by two agencies, the DRC’s Institut National de Recherche Biomédicale (INRB) and the Institute of Tropical Medicine (ITM) in Antwerp. The routine isolation of the causative organisms from patients across the country has proved a great help in picking up the earliest indications of bloodstream infections with this XDR strain of S. typhimurium. With hundreds of blood samples collected from patients in the DRC who were suspected to have sepsis, the emergence of drug resistance to S. typhimurium on an order never before imagined is becoming clear. Scientists have put in place a worldwide effort to trace the continuing development of ST313, and to assess its resistance to antibiotics.
Bioinformatics is becoming more important as it helps detect these signs of invasiveness. Researcher Nicole Wheeler says, “The hope is that in the near future we'll be able to deploy machine learning in a more predictive role to help control the emergence and spread of drug-resistant strains of bacteria such as S. typhimurium.”
Cambridge Professor Gordon Dougan comments: “Studies like this are unique as we are making the bridge between the most important health issues observed in hospitals across the world with in-depth biological research for which we apply cutting edge technologies. Collaborations like this are key and will be important in the future to gain further insights on emerging diseases.”
An African Salmonella typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation. Sandra Van Puyvelde, Derek Pickard, Koen Vandelannoote, Eva Heinz, Barbara Barbé, Tessa de Block, Simon Clare, Eve L. Coomber, Katherine Harcourt, Sushmita Sridhar, Emily A. Lees, Nicole E. Wheeler, Elizabeth J. Klemm, Laura Kuijpers, Lisette Mbuyi Kalonji, Marie-France Phoba, Dadi Falay, Dauly Ngbonda, Octavie Lunguya, Jan Jacobs, Gordon Dougan & Stijn Deborggraeve. Nature Communications, volume 10, Article number: 4280 (2019). https://doi.org/10.1038/s41467-019-11844-z. https://www.nature.com/articles/s41467-019-11844-z