Extensively Drug-Resistant (XDR) Typhoid: Evolution, Prevention, and Its Management.

Typhoid fever is the result of a human host-restricted Salmonella enteric serotype typhi infection that causes enteric fever. Around 21 million people contract typhoid annually, with Pakistan's inhabitants at most risk amongst Asian countries where typhoid remains prevalent. Decades of indiscriminate antibiotic usage has driven the evolution of multidrug-resistant strains and more recently, extensively drug-resistant (XDR) strains of Salmonella enteric serotype typhi. Current reports of extensively drug-resistant typhoid fever outbreak in Pakistan are not only a major concern for Pakistan but also for health authorities worldwide: intercontinental transmission, spread, and replacement of native strains in neighboring countries and a major impediment to Pakistani health care management. The WHO records that there are 5274 cases of extensively drug-resistant (XDR) typhoid fever out of a total of 8188 total cases of typhoid fever reported in Pakistan. The last remaining feasible oral antibiotic that XDR typhoid remains susceptible to is azithromycin; this is a cause of major concern. Additionally, several cases of XDR typhoid fever have also been reported in patients travelling from Pakistan to the USA, UK, and Canada. This review article attempts to raise the issue of XDR typhoid with respect to its epidemiology, prevention, management, and future outlook and stresses a better understanding of antimicrobial stewardship and general surveillance of the disease. Although progress is being made to combat XDR typhoid locally, efficient, unified efforts on a national and international scale are required to contain the XDR outbreak before it is no longer manageable and leads us back to the preantibiotic era.

Akram J ，Khan AS ，Khan HA ，Gilani SA ，Akram SJ ，Ahmad FJ ，Mehboob R ... -  《-》

Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins.

Antibiotic resistance is a major problem in Salmonella enterica serovar Typhi, the causative agent of typhoid. Multidrug-resistant (MDR) isolates are prevalent in parts of Asia and Africa and are often associated with the dominant H58 haplotype. Reduced susceptibility to fluoroquinolones is also widespread, and sporadic cases of resistance to third-generation cephalosporins or azithromycin have also been reported. Here, we report the first large-scale emergence and spread of a novel S Typhi clone harboring resistance to three first-line drugs (chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) as well as fluoroquinolones and third-generation cephalosporins in Sindh, Pakistan, which we classify as extensively drug resistant (XDR). Over 300 XDR typhoid cases have emerged in Sindh, Pakistan, since November 2016. Additionally, a single case of travel-associated XDR typhoid has recently been identified in the United Kingdom. Whole-genome sequencing of over 80 of the XDR isolates revealed remarkable genetic clonality and sequence conservation, identified a large number of resistance determinants, and showed that these isolates were of haplotype H58. The XDR S Typhi clone encodes a chromosomally located resistance region and harbors a plasmid encoding additional resistance elements, including the blaCTX-M-15 extended-spectrum β-lactamase, and carrying the qnrS fluoroquinolone resistance gene. This antibiotic resistance-associated IncY plasmid exhibited high sequence identity to plasmids found in other enteric bacteria isolated from widely distributed geographic locations. This study highlights three concerning problems: the receding antibiotic arsenal for typhoid treatment, the ability of S Typhi to transform from MDR to XDR in a single step by acquisition of a plasmid, and the ability of XDR clones to spread globally.IMPORTANCE Typhoid fever is a severe disease caused by the Gram-negative bacterium Salmonella enterica serovar Typhi. Antibiotic-resistant S Typhi strains have become increasingly common. Here, we report the first large-scale emergence and spread of a novel extensively drug-resistant (XDR) S Typhi clone in Sindh, Pakistan. The XDR S Typhi is resistant to the majority of drugs available for the treatment of typhoid fever. This study highlights the evolving threat of antibiotic resistance in S Typhi and the value of antibiotic susceptibility testing and whole-genome sequencing in understanding emerging infectious diseases. We genetically characterized the XDR S Typhi to investigate the phylogenetic relationship between these isolates and a global collection of S Typhi isolates and to identify multiple genes linked to antibiotic resistance. This S Typhi clone harbored a promiscuous antibiotic resistance plasmid previously identified in other enteric bacteria. The increasing antibiotic resistance in S Typhi observed here adds urgency to the need for typhoid prevention measures.

Klemm EJ ，Shakoor S ，Page AJ ，Qamar FN ，Judge K ，Saeed DK ，Wong VK ，Dallman TJ ，Nair S ，Baker S ，Shaheen G ，Qureshi S ，Yousafzai MT ，Saleem MK ，Hasan Z ，Dougan G ，Hasan R ... -  《mBio》

Continued Outbreak of Ceftriaxone-Resistant Salmonella enterica Serotype Typhi across Pakistan and Assessment of Knowledge and Practices among Healthcare Workers.

Nizamuddin S ，Ching C ，Kamal R ，Zaman MH ，Sultan F ... -  《-》

Update on Extensively Drug-Resistant Salmonella Serotype Typhi Infections Among Travelers to or from Pakistan and Report of Ceftriaxone-Resistant Salmonella Serotype Typhi Infections Among Travelers to Iraq - United States, 2018-2019.

François Watkins LK ，Winstead A ，Appiah GD ，Friedman CR ，Medalla F ，Hughes MJ ，Birhane MG ，Schneider ZD ，Marcenac P ，Hanna SS ，Godbole G ，Walblay KA ，Wiggington AE ，Leeper M ，Meservey EH ，Tagg KA ，Chen JC ，Abubakar A ，Lami F ，Asaad AM ，Sabaratnam V ，Ikram A ，Angelo KM ，Walker A ，Mintz E ... -  《-》

Salmonella enterica Serovar Typhi in Bangladesh: Exploration of Genomic Diversity and Antimicrobial Resistance.

Typhoid fever, caused by Salmonella enterica serovar Typhi, is a global public health concern due to increasing antimicrobial resistance (AMR). Characterization of S Typhi genomes for AMR and the evolution of different lineages, especially in countries where typhoid fever is endemic such as Bangladesh, will help public health professionals to better design and implement appropriate preventive measures. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh during 1999 to 2013 and compared those sequences with data from a recent outbreak in Pakistan reported previously by E. J. Klemm, S. Shakoor, A. J. Page, F. N. Qamar, et al. (mBio 9:e00105-18, 2018, https://doi.org/10.1128/mBio.00105-18), and a laboratory surveillance in Nepal reported previously by C. D. Britto, Z. A. Dyson, S. Duchene, M. J. Carter, et al. [PLoS Negl. Trop. Dis. 12(4):e0006408, 2018, https://doi.org/10.1371/journal.pntd.0006408]. WGS had high sensitivity and specificity for prediction of ampicillin, chloramphenicol, co-trimoxazole, and ceftriaxone AMR phenotypes but needs further improvement for prediction of ciprofloxacin resistance. We detected a new local lineage of genotype 4.3.1 (named lineage Bd) which recently diverged into a sublineage (named Bdq) containing qnr genes associated with high-level ciprofloxacin resistance. We found a ceftriaxone-resistant isolate with the blaCTX-M-15 gene and a genotype distinct from the genotypes of extensively drug-resistant (XDR) isolates from Pakistan. This result suggests a different source and geographical origin of AMR. Genotype 4.3.1 was dominant in all three countries but formed country-specific clusters in the maximum likelihood phylogenetic tree. Thus, multiple independent genetic events leading to ciprofloxacin and ceftriaxone resistance took place in these neighboring regions of Pakistan, Nepal, and Bangladesh. These independent mutational events may enhance the risk of global spread of these highly resistant clones. A short-term global intervention plan is urgently needed.IMPORTANCE Typhoid fever, caused by Salmonella enterica serovar Typhi, is responsible for an estimated burden of approximately 17 million new episodes per year worldwide. Adequate and timely antimicrobial treatment invariably cures typhoid fever. The increasing antimicrobial resistance (AMR) of S Typhi severely limits the treatment options. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh between 1999 and 2013 and compared those sequences with data from a recent outbreak in Pakistan and a laboratory surveillance in Nepal. The analysis suggests that multiple ancestral origins of resistance against ciprofloxacin and ceftriaxone are present in three countries. Such independent genetic events and subsequent dissemination could enhance the risk of a rapid global spread of these highly resistant clones. Given the current treatment challenges, vaccination seems to be the most appropriate short-term intervention to reduce the disease burden of typhoid fever at a time of increasing AMR.

Tanmoy AM ，Westeel E ，De Bruyne K ，Goris J ，Rajoharison A ，Sajib MSI ，van Belkum A ，Saha SK ，Komurian-Pradel F ，Endtz HP ... -  《mBio》