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 0.75x MIC (0.012 to 0.38 microg/ml) with
cefotaxime at the MIC (0.125 to 0.25 microg/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 0.75x MIC (0.012 to 0.38 microg/ml) was combined with
cefotaxime at 2x MIC (0.25 to 0.50 microg/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
ciprofloxacin-plus-
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.