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Publications (2)7.71 Total impact

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    [Show abstract] [Hide abstract] ABSTRACT: Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever) but there are no clinically validated minimum inhibitory concentration (MIC) and disk zone size interpretative guidelines. We studied individual patient data from three randomised controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 Typhi and Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs 214 patients who were treated with azithromycin at a dose of 10-20mg/mL for 5-7 days were analysed. Treatment was successful in 195/214 (91%) with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4-16μg/mL. The proportion of Asian enteric fever isolates with an MIC of ≤ 16μg/mL was 1,392/1,400 (99.5%, 95% CI 98.9-99.7) for Typhi and 207/240 (86.3%, 95% CI 81.2-90.3) (p<0.001) for Paratyphi A. A zone size of ≥13mm to a 5μg azithromycin disk identified Typhi isolates with an MIC ≤16μg/mL with a sensitivity of 99.7%. An azithromycin MIC of ≤16μg/mL or disk inhibition zone size of ≥13mm enabled the detection of susceptible Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in Typhi isolates with an azithromycin MIC>16 μg/mL and to determine MIC and disk breakpoints for Paratyphi A. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Full-text · Article · Mar 2015 · Antimicrobial Agents and Chemotherapy
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    [Show abstract] [Hide abstract] ABSTRACT: Drug 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. We 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. An 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). We 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. Both 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. ISRCTN67946944.
    Full-text · Article · Feb 2008 · PLoS ONE