Analysis of mechanisms involved in reduced susceptibility to ciprofloxacin in Salmonella enterica serotypes Typhi and Paratyphi A isolates from travellers to Southeast Asia

Abstract

Owing to multidrug resistance, quinolones and third-generation cephalosporins are currently used as key antibiotics to combat Salmonella organisms. Therapy failure due to reduced ciprofloxacin susceptibility has been reported in endemic areas, but also in imported disease. Different bacterial resistance mechanisms may result in reduced ciprofloxacin susceptibility. In this study, the presence and expression of different resistance mechanisms resulting in reduced minimum inhibitory concentrations (MICs) for ciprofloxacin were evaluated in 23 blood-culture-derived Salmonella enterica serotypes Typhi and Paratyphi A organisms from ill-returned travellers to Asia. The presence of mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene as well as an activated efflux pump and plasmid-mediated quinolone resistance genes was determined. Resistance selection during therapy and the clonal relatedness of all isolates were established. Efflux pump inhibition did not appear to affect the MICs of ciprofloxacin and activity of the efflux pump appeared to be specific for nalidixic acid. Repeated exposure of the isolates to ciprofloxacin did not result in a significant increase in the MICs for ciprofloxacin. Repetitive sequence-based polymerase chain reaction (rep-PCR) profiles identified five different genotypes, but no correlation with resistance was observed. However, a significant relation was found with geographic region; reduced ciprofloxacin susceptibility was only found in travellers returning from India and Pakistan. All isolates with reduced ciprofloxacin susceptibility had a mutation at position 83 in the QRDR region of the gyrA gene. Plasmid-mediated quinolone resistance was not found. These findings confirm that the reduced ciprofloxacin MIC in S. Typhi and S. Paratyphi A is solely due to an amino acid substitution in the QRDR 'cluster' of the gyrA gene.

Six Cases of Paratyphoid Fever Due to Salmonella Paratyphi A in Travelers Returning from Myanmar Between July 2014 and August 2015

“…8 Hassing and others reported the susceptibility of S. typhi and S. Paratyphi A isolates to ciprofloxacin among travelers to southeast Asia. 9 Isolates from travelers to Indonesia and Cambodia were sensitive to fluoroquinolones; yet, in this report, resistance or reduced susceptibility to fluoroquinolones was found in travelers to India and Pakistan. Meltzer and others reported an outbreak of S. Paratyphi A infection among Israeli travelers to Nepal.…”

Trends in Serotype Distribution and Antimicrobial Susceptibility in Salmonella enterica Isolates from Humans in Belgium, 2009 to 2013

“…S. Typhi isolates display above average resistance to purine synthesis inhibitors, while NalR is encountered in the majority of both S. Typhi (58/112) and Paratyphi A (27/32) isolates. Moreover, 25% of the S. Paratyphi A strains show intermediate ciprofloxacin resistance, which might complicate treatment outcome (8).…”

“…Typhoidal Salmonella enterica serotypes Typhi and Paratyphi A and B are notorious pathogens, restricted to humans and causing 13.5 million annual episodes of typhoid fever, especially in low-and middle-income countries (7). In developed countries, outbreaks of typhoid fever account for Ͻ1% of all infections and are mainly associated with travel (8).…”

Detection of amino acid substitutions in the GyrA protein of fluoroquinolone-resistant typhoidal Salmonella isolates using high-resolution mass spectrometry

“…In the majority of cases, fluoroquinolone resistance in typhoidal Salmonella spp. has been associated with a mutation in the quinolone resistancedetermining region (QRDR) of gyrA, resulting in a single amino acid substitution in the GyrA protein [5,6]. Expression of this mutated gyrA gene (at Ser83) results in low-level resistance to fluoroquinolone antibiotics as well as resistance to nalidixic acid (a closely related 'quinolone' antibiotic).…”