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SUPPLEMENT ARTICLE
Multiple drug (antibiotic) resistance (MDR) has become a major threat to the treatment of typhoid and other infectious diseases.
Since the 1970s, this threat has increased in Salmonella enterica serovar Typhi, driven in part by the emergence of successful genetic
clades, such as haplotype H58, associated with the MDR phenotype. H58 S. Typhi can express multiple antibiotic resistance determi-
Since the introduction of antibiotics in the middle of the last Salmonella enterica serovar Typhi (S. Typhi) is a subtype
century, there has been an increasing appreciation of the threat of the Gram-negative enteric pathogen Salmonella enterica.
of antibiotic resistance [1, 2]. Following the first clinical use of Unlike many other S. enterica serovars, S. Typhi is a human
penicillin, many other antibiotics have been introduced and, in restricted pathogen that, as far as we know, is propagated by
each case, resistance has followed at some level. The threat of human to human spread with no zoonotic reservoir and with a
resistance has been compounded by a dramatic reduction in the limited ability to survive longer term in the environment [4]. S.
rate of introduction of novel classes of antibiotics and an associ- Typhi can persist in water and food contaminated with human
ated drop in investment in the area (https://amr-review.org). We fecal material, but there is no environmentally adapted stage of
are now in an era where the levels of circulating virulent, multi- the bacterial life-cycle such as the formation of spores. The per-
ple drug-resistant (MDR) bacteria threatens healthcare efficacy sistence of S. Typhi in human populations is influenced by clin-
globally. Typhoid treatment was one of the key areas that imme- ically silent carriage within certain individuals (carriers) that
diately benefited from antibiotic usage. This chronic infection can be infected for months and even years with periodic shed-
with the potential for relapse, carriage, and complications was ding of S. Typhi into the environment in contaminated feces.
enormously challenging in terms of clinical management prior Thus, antibiotic usage can influence both acute typhoid disease
to antibiotics. Indeed, antibiotic treatment transformed the and the carrier state. In both states the emergence of antibiotic
clinical management of the disease and the public’s percep- resistance is theoretically possible. Unlike other enteric bacte-
tion of the threat the disease posed. Antibiotics, together with ria, genetic and phenotypic analysis (eg, through the controlled
improved water treatment and better public health manage- challenge of human volunteers) has indicated that S. Typhi is
ment, led to the control of the disease, at least in economically relatively poorly adapted for growth in the human intestine
developed settings. However, typhoid remains in economically [5]. Indeed, many genes, for example, shdA associated with
deprived areas where poverty and poor infrastructure persisted persistence in the intestine are inactivated in S. Typhi and are
[3]. In these same resource-limited settings, the indiscriminate consequently known as pseudogenes [6]. S. Typhi also shows
use of antibiotics has encouraged resistance and selected for vir- limited evidence of recombination with other bacteria, sug-
ulent MDR clades. Thus, antibiotic resistance in typhoid is now gesting the global population of S. Typhi is relatively isolated
a clinical and economic challenge. compared to other enteric bacteria that live free in the intes-
tine or environment [7]. This, theoretically, limits their relative
ability to horizontally acquire genes, including those that are
a
encoded on genetically mobile elements. Nevertheless, over
Z. A. D. and E. J. K. contributed equally.
the past 70 years, multiple antibiotic resistance in S. Typhi has
Correspondence: G. Dougan, Department of Medicine, University of Cambridge, 5th Fl,
Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0SP, United Kingdom (gd312@medschl.cam. emerged as a global threat.
ac.uk).
Clinical Infectious Diseases® 2019;68(S2):S165–70 THE EARLY EMERGENCE OF ANTIBIOTIC
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society
RESISTANCE IN S. TYPHI
of America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Shortly after the introduction of chloramphenicol for the treat-
DOI: 10.1093/cid/ciy1111 ment of typhoid, reports of resistance in S. Typhi began to
Figure 1. Outline genetic structure of XDR S. Typhi in Pakistan. A, Oval outlines represent individual bacteria harboring chromosome (wiggly, green) and plasmid (red and
blue circles) elements. Red and blue triangles represent acquired resistance loci. Small purple triangles represent SNPs in the chromosome associated with resistance. B,
Detailed structures with color codes as per A of the different acquired resistance elements on plasmid and chromosome. Abbreviations: AMR, antimicrobial resistance; MDR,
multiple drug resistance; SNP, single nucleotide polymorphism; XDR, extensively drug resistant.