Abstract
BackgroundDrug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing.ObjectivesWe performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.MethodsAn open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi). Principal FindingsWe enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94–118 hours for gatifloxacin versus 88–112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80–1.26]).Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43–2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant.ConclusionsBoth antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam.Trial RegistrationControlled-Trials.com ISRCTN67946944
Highlights
There are approximately 21 million cases of typhoid fever annually, with more than 210 000 deaths [1]
Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever in regions with high rates of multidrug and nalidixic acid resistance
The extensive antibiotic pressure lead to the selection of single point mutations in the DNA Gyrase A of S. typhi, causing resistance to nalidixic acid and reduced susceptibility to the fluoroquinolones (but formally these isolates are still within the Clinical Laboratory Standard Institute (CLSI) breakpoints for susceptibility) [6]. This resulted in a poor clinical response to treatment with the older generation fluoroquinolones, ofloxacin or ciprofloxacin [7,8]
Summary
There are approximately 21 million cases of typhoid fever annually, with more than 210 000 deaths [1]. The extensive antibiotic pressure lead to the selection of single point mutations in the DNA Gyrase A of S. typhi, causing resistance to nalidixic acid (the prototype quinolone) and reduced susceptibility to the fluoroquinolones (but formally these isolates are still within the Clinical Laboratory Standard Institute (CLSI) breakpoints for susceptibility) [6]. This resulted in a poor clinical response to treatment with the older generation fluoroquinolones, ofloxacin or ciprofloxacin [7,8]. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing
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