In Vitro Synergism of Ciprofloxacin and Cefotaxime against Nalidixic Acid-Resistant Salmonella enterica Serotypes Paratyphi A and Paratyphi B

Abstract

Paratyphoid fever is considered an emerging systemic intracellular infection caused by Salmonella enterica serotypes Paratyphi A, B, and C. We performed in vitro time-kill studies on three clinical isolates of nalidixic acid-resistant Salmonella serotype Paratyphi (NARSP) with different concentrations of ciprofloxacin and cefotaxime to identify combinations of antibiotics with synergistic activity against paratyphoid fever. Furthermore, we identify the frequency of mutations to ciprofloxacin, cefotaxime, and rifampin resistance and also sequenced the gyrA, gyrB, parC, and parE genes to identify the cause of resistance in NARSP. When the activity of ciprofloxacin at 0.75؋ MIC (0.012 to 0.38 g/ml) with cefotaxime at the MIC (0.125 to 0.25 g/ml) against all three NARSP isolates was investigated, synergy was observed at 24 h, and the bacterial counts were reduced by >3 log 10 CFU/ml. This synergy was elongated for up to 72 h in two out of three isolates. When ciprofloxacin at 0.75؋ MIC (0.012 to 0.38 g/ml) was combined with cefotaxime at 2؋ MIC (0.25 to 0.50 g/ml), synergy was prolonged for up to 72 h in all three isolates. Both Salmonella serotype Paratyphi A isolates carried single mutations in codon 83 of the gyrA gene and codon 84 of the parC gene that were responsible for their reduced susceptibility to ciprofloxacin, while no mutations were found in the gyrB or parE gene. The ciprofloxacinplus-cefotaxime regimen was very effective in reducing the bacterial counts at 24 h for all three isolates, and this combination therapy may be helpful in reducing the chance of the emergence of fluoroquinolone-resistant mutants in patients with severe paratyphoid fever.

Prevalence, serotyping and antimicrobials resistance mechanism of Salmonella enterica isolated from clinical and environmental samples in Saudi Arabia

“…Quinolones resistance are usually mediated mainly by point mutations in bacterial gyrase ( gyrA and gyrB ) and topoisomerase IV ( parC and parE ) genes. These mutations lead to block the binding site of topoisomerase or gyrase targeting by antimicrobial agents 34, 35. In the present study point mutations were detected in all quinolones resistant S. enterica isolates ( n  = 5) in both gyrA and parC with large changes in both Para and NS10 isolates leading to complete frame shift of amino acids sequences of proteins in both topoisomerase and gyrase.…”

Revised Ciprofloxacin Breakpoints for Salmonella : Is it Time to Write an Obituary?

“…This resistance to quinolones is caused by amino acid substitutions in the quinolone resistance-determining region of the DNA gyrase, subunit gyrA, gyrB or DNA topoisomerase IV(parC,parE) which are key targets of quinolones [14]. Single mutation in gyrA is said to be responsible for decreased susceptibility to ciprofloxacin whereas combination of 2 or more mutations in gyrA, gyrB, parC and parE makes them resistant [15]. Ciprofloxacin is concentrated in human monocytes and increases their bactericidal activity against intracellular bacteria which may explain why it is still effective in achieving clinical cure in patients with salmonella infections, which is intracellular.…”

Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults

“…Typhi and S . Paratyphi exhibited a synergistic effect[ 13 ] , [ 14 ]; and another recent case report has proposed a combination therapy of meropenem and fosfomycin for highly drug-resistant S . Typhi in a traveler returning from India[ 15 ].…”