The influence of reduced susceptibility to fluoroquinolones in Salmonella enterica serovar Typhi on the clinical response to ofloxacin therapy

Abstract

Background: Infection with Salmonella enterica serovar Typhi (S. Typhi) with reduced susceptibility to fluoroquinolones has been associated with fluoroquinolone treatment failure. We studied the relationship between ofloxacin treatment response and the ofloxacin minimum inhibitory concentration (MIC) of the infecting isolate. Individual patient data from seven randomised controlled trials of antimicrobial treatment in enteric fever conducted in Vietnam in which ofloxacin was used in at least one of the treatment arms was studied. Data from 540 patients randomised to ofloxacin treatment was analysed to identify an MIC of the infecting organism associated with treatment failure.

Principal findings: The proportion of patients failing ofloxacin treatment was significantly higher in patients infected with S. Typhi isolates with an MIC≥0.25 µg/mL compared with those infections with an MIC of ≤0.125 µg/mL (p<0.001). Treatment success was 96% when the ofloxacin MIC was ≤0.125 µg/mL, 73% when the MIC was between 0.25 and 0.50 µg/mL and 53% when the MIC was 1.00 µg/mL. This was despite a longer duration of treatment at a higher dosage in patients infected with isolates with an MIC≥0.25 µg/mL compared with those infections with an MIC of ≤0.125 µg/mL.

Significance: There is a clear relationship between ofloxacin susceptibility and clinical outcome in ofloxacin treated patients with enteric fever. An ofloxacin MIC of ≥0.25 µg/mL, or the presence of nalidixic acid resistance, can be used to define S. Typhi infections in which the response to ofloxacin may be impaired.

Figure 1. The distribution of S. Typhi MIC to ofloxacin in seven RCTs.

Histogram showing the distribution of S. Typhi MICs (<0.06, 0.06, 0.125, 0.25, 0.5 and 1 µg/mL) to ofloxacin over seven individual randomised. The proportion of S. Typhi strains with the corresponding MIC are shaded accordingly, white; study TY1 (1992–1993) n = 19 , very light grey; study CT1 (1993–1994) n = 102 , light grey; study TY2 (1993–1996) n = 103 , mid grey; study DTC (1994–1995) n = 154 , dark grey; study DN (1995–1996) n = 55 , very dark grey; study TY3 (1997–1998) n = 45 and black; study DTY2 (1998–2001) n = 62 .

Figure 2. The relationship between increasing S. Typhi MIC to ofloxacin and clinical failure.

Histogram showing the proportion of enteric fever patients who failed treatment (white columns) or had persistent fever (black columns) (>38°C) for more than seven days after the commencement of treatment. Data was combined from seven randomised clinical trials and is comprised from 540 children and adults recruited with uncomplicated enteric fever. The patients are divided according to the MIC to ofloxacin of the infecting isolate.

Figure 3. The duration of febrile episodes in enteric fever patients infected with S. Typhi organisms with a range of MICs to ofloxacin.

Kaplan Meir curve showing the proportion of patients remaining febrile (>38°C) after the start of treatment with ofloxacin. Data is composed from fever clearance times of 540 children and adults with uncomplicated enteric fever recruited to seven randomised clinical trial and treated with oral ofloxacin. The curves are divided according to the ofloxacin MIC of the infecting isolates and are highlighted on the diagram.