P X TYPHOID

Imported Cases of Extensively Drug-Resistant Salmonella

Simner, Patricia J. PhD; 

To the Editors:

Salmonella enterica serovar Typhi—the cause of typhoid fever—affects approximately 7 million people per year in South Asia.1 Inadequately treated typhoid fever causes a debilitating febrile illness that can persist for weeks, and untreated typhoid fever leads to mortality in about 20% of patients.1

S.Typhi isolates in South Asia frequently belong to the H58 haplotype which contain a multidrug-resistant cassette that generally resides on an IncHI1 plasmid (within transposon Tn2670) or have become chromosomally integrated.2 Specific acquired antimicrobial resistance genes carried by this cassette explain the organism’s resistance profile including (1) blaTEM-1 encoding ampicillin resistance, (2) dfr7, sul1 and sul2 genes encoding trimethoprim-sulfamethoxazole resistance, (3) catA1 encoding chloramphenicol resistance and (4) mutation(s) in gyrA and/or parC leading to fluoroquinolone nonsusceptibility.2 Often, azithromycin, carbapenems and the expanded-spectrum cephalosporins (eg, ceftriaxone, cefixime) are the only remaining treatment options. Azithromycin is relegated to uncomplicated infections due to its poorly sustained serum concentrations, and carbapenem use can be logistically challenging in resource-limited settings, making expanded-spectrum cephalosporins often the only feasible option.

In 2016, a large outbreak of extensively drug-resistant (XDR) S. Typhi of the H58 haplotype began in the Sindh Province of Pakistan.3,4 As of June 2019, over 7900 XDR S. Typhi cases were reported in the region.5 Whole genome sequencing of 87 outbreak isolates revealed remarkable sequence conservation among these isolates and the presence of the previously aforementioned chromosomally integrated multidrug-resistant cassette as well as an IncY plasmid, a promiscuous plasmid that likely originated from Escherichia coli.4 This plasmid contains a qnrS gene capable of further increasing fluoroquinolone minimum inhibitory concentrations as well as blaCTX-M-15, the most common extended-spectrum β-lactamase gene identified worldwide, resulting in ceftriaxone resistance.6

At The Johns Hopkins Hospital, over a 6-month period (December 2018 to May 2019), 3 children spanning the ages of 4–15 years with S. Typhi bloodstream infections were identified with isolates exhibiting resistance to ampicillin, ceftriaxone, trimethoprimsulfamethoxazole resistance and ciprofloxacin. Organism identification was performed by matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker Daltonics, Inc., Billerica, MA), and antimicrobial susceptibility testing was performed on the BD Phoenix Automated System (BD Diagnostics, Sparks, MD). The children were previously healthy and recently visited Pakistan. All 3 presented to medical care with a prolonged febrile illness (median 12 days), significant abdominal pain, and a relatively ill appearance. The median duration of bacteremia after starting antibiotics was 4 days—with the relatively prolonged duration most likely attributable to ineffective empiric ceftriaxone therapy. The 3 patients received meropenem therapy for a duration of 7–14 days with transition to oral azithromycin at a median of 5 days for 2 patients after the clearance of bacteremia, and an appropriate clinical response was observed. All 3 children recovered completely.

In the previous 2 years (January 2016 to November 2018), of the 19 S. Typhi isolates recovered from stool or blood of unique patients (of all ages) at The Johns Hopkins Hospital, none were XDR, suggesting that numbers of imported cases of XDR S. Typhi to our region are increasing. Whole genome sequencing of the 3 XDR isolates at The Johns Hopkins Hospital was performed on the Illumina HiSeq platform (San Diego, CA) and was found to contain the same antimicrobial resistance determinants and IncY plasmid as the 87 isolates previously sequenced from XDR S. Typhi patients in Pakistan.4 The recent increase in imported cases of XDR S. Typhi reminds us of the need to be vigilant for XDR S.Typhi infections. For ill-appearing patients returning from Pakistan with a high pretest probability of typhoid fever, empiric carbapenem therapy should be considered.