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

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          Abstract

          Background

          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.

          Objectives

          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.

          Methods

          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).

          Principal Findings

          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.

          Conclusions

          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.

          Trial Registration

          Controlled-Trials.com ISRCTN67946944

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          Most cited references34

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          Typhoid and paratyphoid fever.

          M. K. Bhan, Rajiv Bahl, Shinjini Bhatnagar (2015)
          Typhoid fever is estimated to have caused 21.6 million illnesses and 216,500 deaths globally in 2000, affecting all ages. There is also one case of paratyphoid fever for every four of typhoid. The global emergence of multidrug-resistant strains and of strains with reduced susceptibility to fluoroquinolones is of great concern. We discuss the occurrence of poor clinical response to fluoroquinolones despite disc sensitivity. Developments are being made in our understanding of the molecular pathogenesis, and genomic and proteomic studies reveal the possibility of new targets for diagnosis and treatment. Further, we review guidelines for use of diagnostic tests and for selection of antimicrobials in varying clinical situations. The importance of safe water, sanitation, and immunisation in the presence of increasing antibiotic resistance is paramount. Routine immunisation of school-age children with Vi or Ty21a vaccine is recommended for countries endemic for typhoid. Vi vaccine should be used for 2-5 year-old children in highly endemic settings.
          Article 0 comments Cited 147 times – based on 0 reviews     Review now
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            Current concepts in the diagnosis and treatment of typhoid fever.

            Zulfiqar Bhutta (2006)
            Article 0 comments Cited 89 times – based on 0 reviews     Review now
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              Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones.

              Magdarina Agtini, John Wain, R. Ochiai … (2007)
              This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83-->Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2008
                Publication date (Electronic): 21 May 2008
                Volume: 3
                Issue: 5
                Electronic Location Identifier: e2188
                Affiliations
                [1 ]Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [2 ]The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [3 ]An Giang Provincial Hospital, Long Xuyen, Vietnam
                [4 ]Dong Thap Provincial Hospital, Cao Lanh, Dong Thap, Vietnam
                [5 ]Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom
                [6 ]The London School of Hygiene and Tropical Medicine, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [7 ]Patan Hospital, Lagankhel, Lalitpur, Nepal
                Cincinnati Children's Hospital Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: TH JF SD PT NS NC KS CD BB JC TS NV TP NR LP HV DD NB ML PB VH CS. Performed the experiments: TH JF SD NS NC CD JC TS NV TP NR LP HV DD NB DL LH NB NH PD ML PB VH NH TN TC CS. Analyzed the data: TH JF PT NS NC KS CD NV TP NR LP HV. Wrote the paper: TH JF PT NS NC KS CD NV TP NR LP HV.

                Article
                Publisher ID: 07-PONE-CT-01857R3
                DOI: 10.1371/journal.pone.0002188
                PMC ID: 2374894
                PubMed ID: 18493312
                SO-VID: 24d07bb9-a533-4e46-a956-d4690204b8ff
                Copyright © Dolecek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 23 July 2007
                Date accepted : 27 March 2008
                Page count
                Pages: 11
                Categories
                Subject: Research Article
                Subject: Infectious Diseases

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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