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.

Author Summary

Typhoid fever is an infection of the bloodstream caused by the organism Salmonella Typhi ( S. Typhi). Treatment with antimicrobials is critical for preventing severe infection and even death, yet antimicrobial resistant organisms have become a problem in many places where typhoid is common. Fluoroquinolones are a group of antimicrobials that are commonly used to treat typhoid, we analysed data from 540 enteric fever patients treated with ofloxacin (a fluoroquinolone) to identify a level of resistance (minimum inhibitory concentration (MIC)) from the infecting organism which is associated with treatment failure. The proportion of patients failing treatment was higher in those infected with a bacterium with an MIC≥0.25 µg/mL, compared with those infections with an MIC of ≤0.125 µg/mL. Treatment success was 96% when the ofloxacin MIC was ≤0.125 µg/mL, yet only 53% when the MIC was 1.00 µg/mL. Our data demonstrates that an S. Typhi bacterium with an ofloxacin MIC of ≥0.25 µg/mL correlates with a poor outcome when treated with this antimicrobial. Therefore, we propose an amendment in the current MIC guidelines for microbiology laboratories to aid clinicians treating typhoid and suggest the use of alternative therapy in these patients.