By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Typhoid fever resulting from antibiotic-resistant strains is being imported from Pakistan and Iraq.

SOURCE: François Watkins LK, Winstead A, Appiah GD, et al. 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. MMWR Morb Mortal Wkly Rep 2020;69:618-622.

In November 2016, infections due to extensively drug-resistant (XDR) Salmonella enterica serotype Typhi emerged in Hyderabad, Pakistan, with rapid spread to the megalopolis of Karachi, where the population is approaching 15 million. XDR Typhi is defined by the presence of resistance to ceftriaxone, ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole. The Centers for Disease Control and Prevention (CDC) subsequently initiated enhanced surveillance for ceftriaxone-resistant Salmonella Typhi in the United States in March 2018.

The CDC identified 30 (31%) XDR infections among 96 Typhi infections in U.S. travelers to or from Pakistan from Jan. 1, 2016, to Aug. 31, 2019. The patients ranged in age from 1 to 41 years (median 11.5 years). The majority had visited Sindh province (which contains Hyderabad and Karachi), but 40% had visited only Punjab province. Among the 24 patients for whom the information was available, none had received typhoid vaccination within the previous five years.

During surveillance, in November 2018 the CDC identified a ceftriaxone-resistant Typhi isolate with a distinctly different antimicrobial susceptibility pattern. Although it was resistant to ceftriaxone, ampicillin, and nalidixic acid, it had intermediate susceptibility to ciprofloxacin and remained fully susceptible to other tested antibiotics, including chloramphenicol and trimethoprim-sulfamethoxazole. The CDC subsequently identified nine additional isolates with similar susceptibility patterns. None of the 10 patients (eight from the United States and two from the United Kingdom) had traveled to Pakistan, but eight of them had traveled to Iraq and one had traveled to Iran. One infant had not traveled, but her asymptomatic father had traveled to Iraq. Of the six patients for whom the information was available, none had received typhoid vaccination prior to travel.

Whole genome sequencing determined that these latter isolates, three of which were tested, were genetically distinct from those associated with travel to Pakistan. Although ceftriaxone resistance to both strains was caused by blaCTX-M-15 carried by an IncY plasmid, the plasmids were not closely related. All Typhi resistant to ceftriaxone in the United States retained susceptibility to both azithromycin and meropenem.

COMMENTARY

The authors pointed out that no ceftriaxone-resistant Salmonella Typhi had ever been isolated within the United States prior to 2018. The 33 cases associated with travel to or from Pakistan are the consequence of the ongoing outbreak of XDR Typhi in that country. As of August 2019, there had been approximately 10,000 cases reported in Sindh province. This resulted in the administration of a novel conjugate typhoid vaccine to 9.4 million children in November 2019. While that effort was implemented in Sindh province, the fact that eight of the 33 cases occurred in relation to or from to areas of Pakistan outside that province is an indication that the outbreak has spread.

In addition to this problem, the identification of a genetically different ceftriaxone-resistant strain of Typhi in association with travel to Iraq (and in one case, Iran) raises further concern. Ceftriaxone resistance in this and the Pakistan-related strain was due to an extended-spectrum β-lactamase carried on a mobile plasmid — making spread of this resistance more likely.

An important lesson: None of the individuals in this report for whom the information was available had undergone vaccination in the years prior to travel.