Typhoid that no first-choice antibiotic can treat, twice over

Typhoid fever kills 12% to 30% of untreated patients. The first-choice
antibiotics are ceftriaxone and ciprofloxacin.

Since 2016, Pakistan has had an outbreak of **extensively drug-resistant
typhoid — resistant to ceftriaxone, ampicillin, chloramphenicol, ciprofloxacin
and trimethoprim-sulfamethoxazole**, leaving only **azithromycin and
carbapenems.**

**Before 2018, no ceftriaxone-resistant Salmonella Typhi case had ever been
identified in the United States.**

Eighteen months

33 cases of ceftriaxone-resistant Typhi, February 2018 – August 2019.
Whole genome sequencing found two distinct clusters:

The second is the finding that changes what a clinician should be thinking.
The Pakistan strain arriving in travellers is an expected consequence of an
outbreak abroad. **An unrelated resistant cluster from Iraq means resistance is
emerging in more than one place at once**, which is why the guidance names
"Pakistan, Iraq, or neighbouring countries" rather than one outbreak.

How they were found

When the Pakistan outbreak was reported, CDC built enhanced surveillance
around it, and the design is worth reading as a template:

• Health departments notify CDC immediately when a typhoid patient reports
  recent travel to Pakistan
• A supplementary interview form for travel and exposures, covering
  patients and household contacts who had been there in the preceding month
• Expedited antimicrobial susceptibility testing on the isolates
• Automatic alerts to CDC epidemiologists whenever a ceftriaxone-resistant
  isolate is identified in the national monitoring system **or uploaded to the
  public sequence database**

The last one is the interesting piece: it watches a public genomic archive for
a result nobody thought to report.

About 350 culture-confirmed typhoid cases reach CDC annually, with isolates
sequenced where laboratories have the resources — which is how relatedness and
the specific resistance genes get identified at all.

What to do

Typhoid is spread faecal-orally, usually by contaminated food or water,
with an incubation of 6–30 days — long enough that a traveller is home and
the trip feels unconnected by the time they fall ill.

• Vaccinate before travelling to areas where typhoid is endemic, and follow
  safe food and water precautions
• Guide treatment by antimicrobial susceptibility testing wherever possible
• Consider travel history when choosing empiric therapy — which is the
  whole practical point. The drug you would reach for first is the one these
  strains are resistant to, and the only clue available on the first day is
  where the patient has been

Source: Centers for Disease Control and Prevention, MMWR.