NEW YORK (GenomeWeb) – A multidrug-resistant typhoid strain known as H58 has been spreading over the last 30 years and displacing antibiotic-sensitive strains, according to an international consortium of researchers led by the Wellcome Trust Sanger Institute.
Reporting today in Nature Genetics, the researchers came to their conclusions by sequencing 1,832 samples of Salmonella Typhi, the bacteria that causes typhoid, collected from 63 countries between 1992 and 2013, and found that 47 percent of the samples originated from a multi-drug resistant strain known as H58.
In addition, the team found a recent and unreported "wave" of transmission in several African countries, which could represent an epidemic.
The H58 multidrug resistant strain is "rapidly spreading around the world," Gordon Dougan, a senior author from the Sanger Institute, said in a statement. "In this study we have been able to provide a framework for future surveillance of this bacterium, which will enable us to understand how antimicrobial resistance emerges and spreads intercontinentally, with the aim to facilitate prevention and control of typhoid through the use of effective antimicrobials, introduction of vaccines, and water and sanitation programs."
Approximately 74 collaborators contributed to sample collection, sequencing, and analysis. Most of the samples were sequenced using Illumina technology, although five H58 isolates were sequenced on the Pacific Biosciences RS II instrument to gain "better resolution of the integration of the large composite transposable element into the chromosome," the researchers reported.
After sequencing, the group aligned reads to the reference genome, identifying 22,145 SNPs that they used to build a phylogenetic tree to track the isolates' relationships and evolution, including the emergence of the lincHI1 plasmid, which confers drug resistance.
The team found that 47 percent, or 853 of the 1,832 isolates, originated from the H58 haplotype, first seen in 1992 in Fiji and Vietnam. The H58 strains are a "unique lineage separated by 151 SNPs" from its nearest non-H58 cluster.
The researchers' analysis indicated a recent clonal expansion of H58 isolates, which seem to be replacing non-H58 isolates.
Of particular concern, the authors identified a potential ongoing and unreported typhoid epidemic in eastern and southern Africa. From 138 isolates from Kenya, Tanzania, Malawi, and South Africa, the team found that the isolates differed by an average of 10 SNPs, indicating a recent clonal expansion.
The genomic data was also supported by recent epidemiological data, which indicated increasing numbers of multi-drug resistant typhoid in those African countries.
In addition, they found that the H58 strains had a higher proportion of drug resistance genes, compared to non-H58 isolates. Resistance genes were found in 68 percent of the H58 isolates compared to just 9 percent of the non-H58 isolates.
The most common resistance genes detected were those that conferred resistance to ampicillin, trimethoprim, sulfonamides, trimethoprim-sulfamethoxazole chloramphenicol, and streptomycin. These genes were each found in over 540 H58 isolates, including in 525 isolates that carried all seven genes.
"In H58, these genes are becoming a stable part of the genome, which means multiply antibiotic resistant typhoid is here to stay," Kathryn Holt, a senior author from the University of Melbourne, said in a statement.
The H58 isolates, while all similar, did show a number of geographical differences. For instance, multidrug-resistant H58 is common in Southeast Asia, and the H58 isolates also have mutations in gyrA, which results in reduced susceptibility to a class of antibiotics called fluoroquinolones, which the authors attribute to the use of those drugs to treat typhoid fever. In South Asia, there are few strains that are multidrug-resistant, however the majority do have the gyrA mutations. Meantime, in Africa, the majority of the recent isolates do not have gyrA mutations, but are resistant to multiple antibiotics.
"H58 requires urgent international attention. Indeed, the arrival of S. Typhi H58 in Africa appears to be transforming the epidemiology of the disease, with [multidrug-resistant] outbreaks of typhoid being reported where the disease was previously unappreciated or absent," the authors wrote.