To the Editor:

In high-income countries, most shigellosis is associated with international travel to areas in which the condition is endemic or with sexual transmission among men who have sex with men (MSM). In cases of shigellosis in which oral antimicrobial treatment is indicated, the recommended first-line oral antimicrobial treatment for shigellosis is ciprofloxacin, with azithromycin as an alternative. Some studies have used whole-genome sequencing to describe the dissemination of antimicrobial-resistant Shigella sonnei and S. flexneri lineages among MSM.1,2 Although resistant to multiple antimicrobials, MSM-related shigella lineages have generally remained susceptible to at least one orally available antimicrobial. To date, sporadic shigellosis clusters that are resistant to all orally available antimicrobials (i.e., extensively drug-resistant shigella) have been reported among MSM.3,4 In the absence of oral antimicrobials, and in severe disease, intravenous treatment with ceftriaxone may be the only alternative treatment option.

In Australia, shigellosis is a notifiable disease under public health legislation. The Microbiological Diagnostic Unit Public Health Laboratory receives all shigella isolates in the state of Victoria, Australia (population, approximately 6.4 million). Isolates undergo antimicrobial susceptibility testing and routine whole-genome sequencing. Details of the methods are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.

Figure 1. Figure 1. Phylogenomic Analysis of Shigella sonnei Isolates in Victoria, Australia, January 2018 through May 2019. Panel A shows a maximum-likelihood tree of 644 S. sonnei isolates received at the Microbiological Diagnostic Unit Public Health Laboratory between January 1, 2016, and May 31, 2019. Of the 644 genomes, 315 formed the BAPS (Bayesian analysis of population structure) 1 lineage, and of these 315 genomes, 171 were extensively drug-resistant (resistant to ciprofloxacin, azithromycin, trimethoprim–sulfamethoxazole, and ampicillin) (see the data set provided in the Supplementary Appendix). The tree was constructed with the use of IQ-TREE software, version 1.6.12 (midpoint-rooted), with a generalized time-reversible model of nucleotide substitution and was based on an input alignment of 7456 single-nucleotide polymorphisms obtained from whole-genome comparisons across the 644 genomes. The BAPS lineages were previously defined by Ingle et al.2 The heat map on the right shows patient sex, as well as phenotypic resistance profiles next to their corresponding genotypic mutations for resistance to ciprofloxacin (number of mutations in quinolone resistance-determining region [QRDR]), azithromycin (presence of mphA), trimethoprim (presence of any dfrA gene), sulfonamides (presence of any sul gene), and ampicillin (presence of any bla gene). The scale bar represents the number of nucleotide substitutions (adjusted for constant sites). Panel B shows a timeline of S. sonnei isolates obtained during the study period, stratified according to BAPS lineage, and shows the increase in BAPS 1 isolates from late 2018. BAPS 3 isolates represent the previously identified MSM-associated S. sonnei lineage in Australia.2

Between February 1, 2018, and May 31, 2019, a total of 184 isolates of extensively drug-resistant S. sonnei were identified from 12 female patients and 172 male patients in Victoria (Figure 1). Phylogenomic analysis indicated that 171 of the isolates formed a distinct clonal lineage within the broader population of S. sonnei, with a median core genome difference of 9 single-nucleotide polymorphisms (interquartile range, 5 to 14), suggesting that S. sonnei of this lineage had been transmitted among men (Fig. S1 in the Supplementary Appendix). Isolates in this lineage harbored triple mutations in the quinolone resistance–determining region (the data set is provided in the Supplementary Appendix), as well as a multidrug-resistant plasmid that was highly related to a plasmid that had previously been described in MSM-associated shigella isolates.1,2 We found more than 99% concordance between the genotypic data and the phenotypic data. These extensively drug-resistant isolates fell within a lineage that had previously been associated with travel to the Indian subcontinent, rather than the major globally circulating MSM-associated S. sonnei lineage that had formerly been identified in Australia (BAPS 3 in Figure 1) and in the United Kingdom.2 On the basis of our epidemiologic data, we know that this clone was circulating locally in January 2016 but did not emerge as a dominant MSM-associated lineage until mid-2018.

The emergence and spread of extensively drug-resistant shigella among MSM has clinical and public health implications. If an initial diagnosis of shigellosis is made with a culture-independent diagnostic test, reflex stool culture and antimicrobial susceptibility testing should be performed to maintain effective surveillance of resistance and to inform treatment, if indicated.5 Given the propensity of MSM-associated shigella to spread around the globe, our findings have relevance to other countries, and clinicians should be aware of the emerging potential for clinical failure of empirical oral antimicrobial agents.

Deborah Williamson, M.D., Ph.D.

Danielle Ingle, Ph.D.

Benjamin Howden, M.D., Ph.D.

University of Melbourne, Melbourne, VIC, Australia

[email protected]

Supported by a grant (APP1147735) from the National Health and Medical Research Council , Government of Australia. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

A list of contributors is provided in the Supplementary Appendix, available at NEJM.org.