Resistance to antimicorbial agents in Salmonella typhi in Vietnam: Clinical response to therapy and molecular mechanisms: Clinical response to therapy and molecular mechanisms

In 1989 1% of isolates of 8. typhi (ST) in Vietnam were multi-drug resistant (MDR) (Amp. Chlor. Trim. Tel. Sulphon.), by 1993 85% of ST were resistant to these antibiotics. In 1992 fluoroquinolones uses became widespread, and rapidly quinolone resistance was reported from the Mekong Delta of Vietnam. By 1997 20% of isolates were resistant. In a clinical trial of 150 patients with uncomplicated typhoid randomised to 2 or 3 days of loxacin (10mg/kg/day), 18 quinolone (nalidixic acid NAR) resistant ST were isolated. The median (range) fever clearance time was 156 (30-366) hours in patients infected with NARST and 84 (12-378) hours in those infected with NAS ST (p ≤ 0.001). 6/18 patients with NAR isolated required retreatment compared with 1/132 patients with NASST, relative risk (95%Cl) 44 (5.6-345) (p ≤ 0.0001). These important clinical differences between the NAR and NAS isolated were noted despite similar MICs. By plasmid extraction and transfer experiments we have demonstrated that MDR in S. typhi in Vietnam is mediated by large molecular weight transferable plasmid. In 1992 there were six distinct plasmid patterns extracted from 22 S. typhi isolates. In 1996 there were only 2 plasmid patterns seen in 19 ST strains. PCR and SSCP of the quinolone resistant determining gyrA gene of S. typhi from 20 NAR isolates revealed two novel point mutations. The first, at nucleotide 97 caused an amino acid change Asp ⇒ Gly (n=17). The second, at nucleotide 83 caused a change Ser ⇒ Phe (n=3). There has been a rapid emergence of MDR ST strains during the 1990’s in the Mekong delta of Vietnam. This is plasmid mediated. Of increasing concern is the development of chromosomally mediated quinolone resistance. There are important differences in the treatment response between NARand NARinfections, despite similar in vitro sensitivities. The persistence of MDR strains and the emergence of quinolone resistant S. typhi may render this important pathogen treatable only with expensive third generation cephalosporins in the near future.