Mechanisms of Multidrug Resistance in Salmonella Typhi and Paratyphi A
Genetic Basis of Resistance
Multidrug-resistant (MDR) enteric fever caused by Salmonella Typhi and Paratyphi A develops through acquisition of resistance genes carried on mobile genetic elements, particularly plasmids and integrons, combined with chromosomal mutations that confer fluoroquinolone resistance. 1, 2
Plasmid-Mediated Resistance
A single 180 kb non-conjugative plasmid carries multiple resistance genes in approximately 71% of MDR S. Typhi isolates, encoding resistance to chloramphenicol (catA gene), ampicillin (blaTEM-1 or blaTEM-116 genes), trimethoprim-sulfamethoxazole (dfrA7, dfrA15, sul1, sul2 genes), and streptomycin (strA-strB genes). 1, 3
The remaining 28.6% of MDR isolates lack plasmids, suggesting chromosomal integration of resistance determinants. 1
Integron-Associated Resistance
Class 1 integrons containing the dfrA7 gene cassette are the primary mechanism for trimethoprim resistance in MDR S. Typhi, representing the first molecular characterization of integron-mediated resistance in these organisms from endemic regions. 2
These integrons facilitate horizontal gene transfer and accumulation of multiple resistance cassettes, enabling rapid spread of MDR phenotypes. 2
Fluoroquinolone Resistance Mechanisms
Fluoroquinolone resistance, now exceeding 95% in endemic regions, results from chromosomal point mutations in DNA gyrase and topoisomerase IV genes rather than plasmid-mediated mechanisms. 4, 5
Specific Mutations
Mutations in gyrA, gyrB, parC, and parE genes reduce the binding affinity of quinolones to their target enzymes, as demonstrated by molecular docking studies showing decreased binding to mutated gyrase A compared to wild-type. 4, 3
Nalidixic acid resistance (present in 91.9% of isolates) serves as a marker for decreased ciprofloxacin susceptibility (DCS), though 94% of nalidixic acid-resistant isolates remain technically "susceptible" by MIC criteria (<0.5 μg/mL), creating a dangerous discordance between laboratory results and clinical outcomes. 6, 5
Clinical Implications of DCS
Isolates with DCS are associated with poorer clinical outcomes and treatment failures despite appearing susceptible on standard disc diffusion testing, particularly among travelers to South and Southeast Asia where fluoroquinolone resistance increased from 19% in 1999 to 59% in 2008. 5
Ciprofloxacin disc testing is unreliable; isolates must be nalidixic acid-sensitive to be truly fluoroquinolone-susceptible, requiring MIC determination for accurate assessment. 7
Emerging Azithromycin Resistance
Azithromycin resistance is emerging as a concerning trend, with only 46% of isolates showing full susceptibility, 31% resistant, and 21% showing intermediate susceptibility in recent surveillance. 6
- This represents a 4- to 10-fold increase in MIC90 values for azithromycin over the past decade, threatening the efficacy of this first-line agent for uncomplicated cases from high-resistance regions. 5
Geographic Variation in Resistance Patterns
Resistance patterns show striking regional variation, with South and Southeast Asia demonstrating the highest rates of fluoroquinolone resistance and ESBL production. 5
Among international travelers, 79% of typhoid cases reported foreign travel within 30 days before symptom onset, with highest risk for those visiting the Indian subcontinent. 5
Regional variation in ETEC fluoroquinolone resistance shows higher rates in India compared with Central America, with EAEC isolates from Central America showing increased resistance across most antibiotics tested. 5
Preserved Susceptibility Patterns
Despite widespread MDR, all isolates remain susceptible to ceftriaxone and third-generation cephalosporins, with no resistance determinants detected by whole genome sequencing. 4, 3
Susceptibility to older agents has paradoxically improved, with 90% susceptible to ampicillin and 95% to co-trimoxazole, suggesting these antibiotics may regain utility in regions where resistance pressure has decreased. 6
Chloramphenicol susceptibility remains high (100% in some studies), though the catA1 gene is present in MDR strains, indicating potential for rapid resistance emergence if usage increases. 3
Molecular Epidemiology
Pan-genome analysis reveals that S. Typhi has a closed pan-genome (Bpan = 0.09) with low genetic diversity (Simpson's diversity index 0.51), where core genes are enriched in metabolic functions while accessory genes carry pathogenesis and antimicrobial resistance determinants. 3
PFGE analysis demonstrates clonal spread of MDR strains, with five of seven MDR isolates containing class 1 integrons showing identical PFGE patterns, indicating successful dissemination of specific resistant clones. 2
The strong association between AMR profiles and pulsotypes is useful for controlling organism spread through appropriate epidemiological intervention. 1
Critical Clinical Pitfall
The most dangerous aspect of current resistance patterns is the discordance between laboratory "susceptibility" and clinical failure with fluoroquinolones, where isolates with DCS appear susceptible by standard testing but cause treatment failures, particularly when ciprofloxacin is used empirically for cases from South/Southeast Asia. 5, 7