Antibiotics are an effective treatment for typhoid. The discovery of antibiotics was ground-breaking for the treatment of typhoid, providing the first medication to clear the bacterial infection. Mortality rates decreased dramatically from around 26 percent to just one percent. But it didn’t take long for the bacteria to evolve mechanisms to resist the antibiotic treatments. Currently, there are Salmonella Typhi strains that are resistant to each major antibiotic. Development of new antibiotics and prudent use of existing antibiotics are important actions, but ultimately antibiotics are only a short-term way to fight typhoid. The best way to stop typhoid is through an integrated prevention and treatment strategy that including vaccines and water, sanitation, and hygiene improvements. Such measures would prevent typhoid cases, thereby decreasing the use of antibiotics and slowing the development of antibiotic resistance across a wide range of bacterial pathogens.
Antibiotics used to treat typhoid
Several classes of antibiotics have been used to effectively treat typhoid. The first-line treatments are chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. S. Typhi strains that are resistant to all three of these antibiotics are classified at multidrug resistant (MDR). Treatment of MDR strains requires other classes of antibiotics including fluoroquinolones (ciprofloxacin and ofloxacin), macrolides (azithromycin), or third-generation cephalosporins such as ceftriaxone. Some alternative antibiotics are more expensive, making them cost-prohibitive in low-income areas, or have adverse side-effects that preclude their use in children.
Antibiotic recommendations take into account if MDR strains are endemic in the area. When laboratory culture is possible, treatment is based on the resistance data of the strain isolated from the patient. However, patients often self-treat with antibiotics that are available without prescription from local pharmacies and only come to the hospital in cases where self-treatment has not resolved the infection.
Timeline of antibiotic resistance in S. Typhi
The first chloramphenicol-resistant S. Typhi were reported in the late 1960s, about two decades after its introduction. Doctors then resorted to using ampicillin and trimethoprim-sulfamethoxazole, leading to emergence of MDR strains with resistance to all three first-line antibiotics in the late 1980s. Recommended usage of the fluoroquinolone ciprofloxacin as an alternative antibiotic in areas with high MDR prevalence resulted in the emergence of strains with decreased susceptibility to ciprofloxacin within a short time period. Strains with resistance to azithromycin and ceftriaxone have also been reported in the past decade. Strains that are MDR and also resistant to ciprofloxacin, azithromycin, or ceftriaxone have also been reported.
Geographical distribution of antibiotic resistant strains
The distribution of antibiotic resistant strains mirrors the antibiotic usage in different areas. In South and Southeast Asia, MDR S. Typhi strains are considered endemic. Thus the recommended treatment switched from first-line antibiotics to fluoroquinolones and the prevalence of MDR strains decreased as strains with reduced susceptibility to fluoroquinolones increased over the same time frame. Empirical data suggest that this trend would quickly reverse upon reintroduction of first-line treatments, especially with so many MDR isolates in circulation globally. Of note, many strains also appeared with both MDR and reduced susceptibility to fluoroquinolones. In contrast, in African areas that continued to use only first-line antimicrobials, reduced susceptibility to fluoroquinolones has not been observed as frequently while MDR remains prevalent. Antibiotic resistance data from South America is comparatively lacking, although susceptible S. Typhi are still frequently observed in this area. You can explore the geographical distribution of antibiotic resistance in our global collection of S. Typhi.
Genetic basis of resistance
The acquisition of resistance to antibiotics is associated with genetic changes to the bacterium. In the case of MDR, this is usually due to the acquisition of cat, dfr, sul, and blaTEM genes on a plasmid or integrated into the chromosome. Likewise, resistance to ceftriaxone is associated with acquisition of extended-spectrum beta-lactamase (ESBL) genes and azithromycin resistance is associated with acquisition of the mphA gene. Fluoroquinolone resistance is different in that reduced susceptibility is usually associated with single nucleotide polymorphisms (SNPs) in the quinolone resistance determining region (QRDR) of the gyrA, gyrB, parC, and parE genes in the chromosome. Occasionally, fluoroquinolone resistance can be caused by plasmid acquired genes such as qnr.
H58, a dominant multidrug resistant (MDR) strain, is spreading globally
While many genetically distinct MDR strains of S. Typhi have been observed sporadically around the world, these strains tended to stay local. A new MDR strain, called H58, emerged in the 1990s and spread across Asia and Africa. Currently, the majority of all global MDR strains belong to the H58 genotype. Sixty-eight percent of H58 in our collection are MDR. The resistance genes in H58 originated from the IncHI1-PST6 plasmid and have transferred to the chromosome multiple times in parallel events in different lineages. In areas with high fluoroquinolone usage, H58 strains have additionally acquired SNPs in the quinolone resistance determining regions, conferring reduced susceptibility to ciprofloxacin. H58 appears to have a competitive advantage over other strains, but the reason for this dominance remains under investigation. You can explore the geographical distribution of H58 in our global collection of S. Typhi.
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