A Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and Adults in Vietnam

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

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections

“…A single daily dose of 10 mg/kg for 7 days has achieved cure in more than 90% of patients and short fever clearance times (341,480,537,538). Gatifloxacin targets both DNA gyrase and topoisomerase IV.…”

“…The immunomodulatory effects of azithromycin may also be important by reversing the immunoparalysis seen in typhoid (28,29,560). Although some initial clinical studies were disappointing (561), subsequent randomized controlled trials have confirmed azithromycin to be equivalent or superior to chloramphenicol, fluoro-quinolones, and extended-spectrum cephalosporins for the management of uncomplicated typhoid fever and associated with a prompt resolution of clinical symptoms and low prevalence of relapse and convalescent fecal carriage (444,469,473,501,511,516,538). Doses have varied between 10 and 20 mg/kg/day for between 5 and 7 days, and the optimum dose and duration are yet to be determined.…”

First Report of Salmonella enterica Serotype Paratyphi A Azithromycin Resistance Leading to Treatment Failure

“…Azithromycin has been used in the treatment of infections with S. Typhi and some enteric infections, and the accepted BSAC breakpoint MIC is 16 mg/liter for wild-type isolates. Azithromycin is suggested as an alternative to ciprofloxacin for treatment of cases that show reduced susceptibility to fluoroquinolones or treatment failure (2,8,9,18). Chayani et al recently showed that azithromycin was active against Salmonella and Shigella species, showing 100% sensitivity by the Etest and 83.33% by the disk diffusion methods (6).…”

La fièvre typhoïde n’est plus aussi simple à soigner

“…Un traitement hybride (ofloxacine à 15 mg/kg/j pendant 7 jours et azithromycine à 10 mg/kg/j pendant les 3 premiers jours) donnait des résultats intermédiaires. [30,31]. La gatifloxacine est une nouvelle fluoroquinolone qui a démontré une SYNTHÈSE REVUES activité bactéricide rapide sur les souches Cip SD et dont les CMI sont un peu plus faibles que celles de la ciprofloxacine sur ces mêmes souches Cip SD [26,31].…”

“…[30,31]. La gatifloxacine est une nouvelle fluoroquinolone qui a démontré une SYNTHÈSE REVUES activité bactéricide rapide sur les souches Cip SD et dont les CMI sont un peu plus faibles que celles de la ciprofloxacine sur ces mêmes souches Cip SD [26,31]. Au cours de ces deux essais, l'échec thérapeutique était documenté pour 3,5 % à 9 % des patients traités par la gatifloxacine (défervescence thermique obtenue entre 92 et 106 heures en moyenne), 9 % des patients traités par l'azithromycine (défervescence thermique obtenue en 106 heures), et 37,6 % des patients traités par le céfixime (défervescence thermique obtenue en 138 heures).…”