Fitness benefits in fluoroquinolone-resistant Salmonella Typhi in the absence of antimicrobial pressure

Abstract

Fluoroquinolones (FQ) are the recommended antimicrobial treatment for typhoid, a severe systemic infection caused by the bacterium Salmonella enterica serovar Typhi. FQ-resistance mutations in S. Typhi have become common, hindering treatment and control efforts. Using in vitro competition experiments, we assayed the fitness of eleven isogenic S. Typhi strains with resistance mutations in the FQ target genes, gyrA and parC. In the absence of antimicrobial pressure, 6 out of 11 mutants carried a selective advantage over the antimicrobial-sensitive parent strain, indicating that FQ resistance in S. Typhi is not typically associated with fitness costs. Double-mutants exhibited higher than expected fitness as a result of synergistic epistasis, signifying that epistasis may be a critical factor in the evolution and molecular epidemiology of S. Typhi. Our findings have important implications for the management of drug-resistant S. Typhi, suggesting that FQ-resistant strains would be naturally maintained even if fluoroquinolone use were reduced.DOI: http://dx.doi.org/10.7554/eLife.01229.001

Fitness cost of antibiotic susceptibility during bacterial infection

“…Other factors, such as the host's diet, could also play a role in maintaining intrinsic antibiotic resistance genes, because foods (45) such as sweet potatoes and coffee contain caffeic acid, a compound that has an antimicrobial activity toward P. aeruginosa (46). In conclusion, the findings that intrinsic and acquired antibiotic resistance genes are associated with increased in vivo fitness of P. aeruginosa, A. baumannii, and V. cholerae in four different experimental infection settings, along with recent reports about the lack of fitness costs associated with antibiotic resistance in S. enterica serovar Typhimurium (47) and E. coli (48), emphasize the necessity to effectively control the emergence of antibiotic-resistant pathogens as well as the development of alternative approaches to prevent and treat infections. Last, our findings point to additional potential consequences, wherein virulent strains of serious microbial pathogens that are both more drug-resistant and more pathogenic may be establishing themselves as the predominant organisms able to infect at-risk humans.…”

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections

“…Studies with whole-genome sequencing of global Salmonella serovar Typhi collections have shown that a particular haplotype, H58, is more likely to be MDR and to have intermediate susceptibility to ciprofloxacin (530,531). This haplotype has become dominant in many regions and may have a competitive advantage compared with other haplotypes (532)(533)(534)(535)(536).…”

Chromosome-Mediated Multidrug Resistance in Salmonella enterica Serovar Typhi

“…Notably, 11 of the 18 MDR S. Typhi isolates from Bangladesh analyzed in this study have developed resistance to high-level fluoroquinolone by alterations in gyrase A (S83F and D87G) and enhanced efflux pumps (9). High-level fluoroquinolone resistance on salmonellae may have a prohibitive fitness cost (29); however, fluoroquinolone-resistant S. Typhi strains may have a fitness benefit even in the absence of antimicrobial pressure (30). Thus, intensive surveillance is necessary to monitor the dissemination of the S. Typhi strains that bear chromosome-mediated resistance to multiple first-line antimicrobials and fluoroquinolone for the treatment of typhoid fever.…”