High-resolution single nucleotide polymorphism analysis distinguishes recrudescence and reinfection in recurrent invasive nontyphoidal Salmonella typhimurium disease.
BACKGROUND
Bloodstream infection with invasive nontyphoidal Salmonella (iNTS) is common and severe among human immunodeficiency virus (HIV)-infected adults throughout sub-Saharan Africa. The epidemiology of iNTS is poorly understood. Survivors frequently experience multiply recurrent iNTS disease, despite appropriate antimicrobial therapy, but recrudescence and reinfection have previously been difficult to distinguish.


METHODS
We used high-resolution single nucleotide polymorphism (SNP) typing and whole-genome phylogenetics to investigate 47 iNTS isolates from 14 patients with multiple recurrences following an index presentation with iNTS disease in Blantyre, Malawi. We isolated nontyphoidal salmonellae organisms from blood (n = 35), bone marrow (n = 8), stool (n = 2), urine (n = 1), and throat (n = 1) samples; these isolates comprised serotypes Typhimurium (n = 43) and Enteritidis (n = 4).


RESULTS
Recrudescence with identical or highly phylogenetically related isolates accounted for 78% of recurrences, and reinfection with phylogenetically distinct isolates accounted for 22% of recurrences. Both recrudescence and reinfection could occur in the same individual, and reinfection could either precede or follow recrudescence. The number of days to recurrence (23-486 d) was not different for recrudescence or reinfection. The number of days to recrudescence was unrelated to the number of SNPs accumulated by recrudescent organisms, suggesting that there was little genetic change during persistence in the host, despite exposure to multiple courses of antibiotics. Of Salmonella Typhimurium isolates, 42 of 43 were pathovar ST313.


CONCLUSIONS
High-resolution whole-genome phylogenetics successfully discriminated recrudescent iNTS from reinfection, despite a high level of clonality within and among individuals, giving insights into pathogenesis and management. These methods also have adequate resolution to investigate the epidemiology and transmission of this important African pathogen.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Chinyere K
CK
Okoro
Robert A
RA
Kingsley
Michael A
MA
Quail
Anstead M
AM
Kankwatira
Nicholas A
NA
Feasey
Julian
J
Parkhill
Gordon
G
Dougan
Melita A
MA
Gordon
D000293:Adolescent; D000328:Adult; D000349:Africa; D000368:Aged; D000369:Aged, 80 and over; D001431:Bacteriological Techniques / Q000379:methods*; D001769:Blood / Q000382:microbiology; D001853:Bone Marrow / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D005260:Female; D005838:Genotype; D006801:Humans; D008295:Malawi; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D010614:Pharynx / Q000382:microbiology; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012480:Salmonella Infections / Q000175:diagnosis* / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D014556:Urine / Q000382:microbiology; D055815:Young Adult