Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial

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We aimed to investigate whether gatifloxacin, a new generation and affordable fluoroquinolone, is better than chloramphenicol for the treatment of uncomplicated enteric fever in children and adults.We did an open-label randomised superiority trial at
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  Gatifloxacin versus chloramphenicol for uncomplicated entericfever: an open-label, randomised, controlled trial Amit Arjyal a , Buddha Basnyat a,* , Samir Koirala a , Abhilasha Karkey a , Sabina Dongol a , Krishna Kumar Agrawaal a , Nikki Shakya a , Kabina Shrestha a , Manish Sharma a , SanjuLama a , Kasturi Shrestha a , Nely Shrestha Khatri a , Umesh Shrestha a , James I Campbell b,c , Stephen Baker b,c , Jeremy Farrar b,c , Marcel Wolbers b,c , and Christiane Dolecek b,c,d a Oxford University Clinical Research Unit–Patan Academy of Health Sciences, Kathmandu,Nepal b The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, OxfordUniversity Clinical Research Unit, Ho Chi Minh City, Vietnam c Centre for Tropical Medicine, University of Oxford, Oxford, UK d London School of Hygiene and Tropical Medicine, London, UK Summary Background— We aimed to investigate whether gatifloxacin, a new generation and affordablefluoroquinolone, is better than chloramphenicol for the treatment of uncomplicated enteric fever inchildren and adults. Methods— We did an open-label randomised superiority trial at Patan Hospital, Kathmandu,Nepal, to investigate whether gatifloxacin is more effective than chloramphenicol for treatinguncomplicated enteric fever. Children and adults clinically diagnosed with enteric fever receivedeither gatifloxacin (10 mg/kg) once a day for 7 days, or chloramphenicol (75 mg/kg per day) infour divided doses for 14 days. Patients were randomly allocated treatment (1:1) in blocks of 50,without stratification. Allocations were placed in sealed envelopes opened by the study physicianonce a patient was enrolled into the trial. Masking was not possible because of the differentformulations and ways of giving the two drugs. The primary outcome measure was treatmentfailure, which consisted of at least one of the following: persistent fever at day 10, need for rescuetreatment, microbiological failure, relapse until day 31, and enteric-fever-related complications.The primary outcome was assessed in all patients randomly allocated treatment and reportedseparately for culture-positive patients and for all patients. Secondary outcome measures werefever clearance time, late relapse, and faecal carriage. The trial is registered oncontrolled-trials.com, number ISRCTN 53258327. Findings— 844 patients with a median age of 16 (IQR 9–22) years were enrolled in the trial andrandomly allocated a treatment. 352 patients had blood-culture-confirmed enteric fever: 175 weretreated with chloramphenicol and 177 with gatifloxacin. 14 patients had treatment failure in thechloramphenicol group, compared with 12 in the gatifloxacin group (hazard ratio [HR] of time tofailure 0·86, 95% CI 0·40–1·86, p=0·70). The median time to fever clearance was 3·95 days (95% © 2011 Elsevier Ltd. All rights reserved. * Correspondence to: Dr Buddha Basnyat, Oxford University Clinical Research Unit–Patan Academy of Health Sciences, Kathmandu,Nepal rishibas@wlink.com.np.This document was posted here by permission of the publisher. At the time of deposit, it included all changes made during peerreview, copyediting, and publishing. The U.S. National Library of Medicine is responsible for all links within the document and forincorporating any publisher-supplied amendments or retractions issued subsequently. The published journal article, guaranteed to besuch by Elsevier, is available for free, on ScienceDirect. Sponsored document from The Lancet Infectious Diseases Published as: Lancet Infect Dis  . 2011 June ; 11(6): 445454.  S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t    CI 3·68–4·68) in the chloramphenicol group and 3·90 days (3·58–4·27) in the gatifloxacin group(HR 1·06, 0·86–1·32, p=0·59). At 1 month only, three of 148 patients were stool-culture positive inthe chloramphenicol group and none in the gatifloxacin group. At the end of 3 months only oneperson had a positive stool culture in the chloramphenicol group. There were no other positivestool cultures even at the end of 6 months. Late relapses were noted in three of 175 patients in theculture-confirmed chloramphenicol group and two of 177 in the gatifloxacin group. There were noculture-positive relapses after day 62. 99 patients (24%) experienced 168 adverse events in thechloramphenicol group and 59 (14%) experienced 73 events in the gatifloxacin group. Interpretation— Although no more efficacious than chloramphenicol, gatifloxacin should be thepreferred treatment for enteric fever in developing countries because of its shorter treatmentduration and fewer adverse events. Funding— Wellcome Trust. Introduction Enteric fever is a disease that predominantly affects children and is caused by the faecal–oral transmission of Salmonella enterica  serotype Typhi ( S typhi ) and Salmonella enterica Paratyphi A ( S paratyphi  A). There are an estimated 26 million infections and over 200 000deaths caused by the disease worldwide each year. In parts of south Asia, the incidence of enteric fever in children can be as high as 573 cases per 100 000 person years.Chloramphenicol was the standard treatment for enteric fever from the 1950s until thedevelopment and spread of multidrug resistant (MDR; defined as resistance to all first-lineantibiotics: chloramphenicol, amoxicillin, and co-trimoxazole) S typhi  and S paratyphi  A inthe early 1990s. Subsequently, fluoroquinolones became first choice for the treatment of enteric fever. However, increased resistance to the older generation fluoroquinolones(ciprofloxacin and ofloxacin) has emerged. This reduces the options for treatment, and raisesthe spectre of fully resistant enteric fever.Conflicting reports have emerged from randomised controlled trials with relatively smallsample sizes that assessed older fluoroquinolones (ciprofloxacin and ofloxacin) versuschloramphenicol for the treatment of enteric fever. Additionally, no trials have been done toinvestigate the efficacy of chloramphenicol versus a newer fluoroquinolone, such asgatifloxacin, in the treatment of enteric fever in children. Recent reports suggest a generaldecline in the prevalence of MDR typhoid fever in Asia, and two recent studies of patientswith enteric fever in Kathmandu, Nepal reported a low prevalence of chloramphenicolresistance in S typhi  and S paratyphi  A isolates: nine (1·7%) in 522 strains of S typhi  andthree (1·2%) of 247 strains of S paratyphi  A.Gatifloxacin was effective in the treatment of nalidixic-acid-resistant enteric fever in twoprevious randomised trials done in Nepal and Vietnam. The drug targets both DNA gyraseand topoisomerase IV, and hence is less inhibited by the common mutations of the gyrA gene of S typhi  than are ciprofloxacin or ofloxacin.We designed a randomised controlled trial to assess whether gatifloxacin had superiorefficacy compared with chloramphenicol in adults and children with uncomplicated entericfever in Nepal. Arjyal et al.Page 2Published as:  Lancet Infect Dis . 2011 June ; 11(6): 445–454.  S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t    Methods Patients The study physicians enrolled patients who presented to the outpatient or emergencydepartment of Patan Hospital, Lalitpur, Nepal from May 2, 2006, to August 30, 2008.Patients with fever for more than 3 days who were clinically diagnosed to have enteric fever(undifferentiated fever with no clear focus of infection on preliminary physical exam andlaboratory tests) whose residence was in a predesignated area of about 20 km 2  in urbanLalitpur and who gave fully informed written consent were eligible for the study. Exclusioncriteria were pregnancy or lactation, age under 2 years or weight less than 10 kg, shock, jaundice, gastrointestinal bleeding, or any other signs of severe typhoid fever, previoushistory of hypersensitivity to either of the trial drugs, or known previous treatment withchloramphenicol, quinolone antibiotic, third generation cephalosporin, or macrolide within 1week of hospital admission. Patients who had received amoxicillin or co-trimoxazole wereincluded as long as they did not show evidence of clinical response. Ethical approval wasgranted by both Nepal Health Research Council and Oxford Tropical Research EthicsCommittee. Randomisation and masking Randomisation was done in blocks of 50 without stratification by an administrator otherwisenot involved in the trial. The random allocations were placed in sealed opaque envelopes,which were kept in a locked drawer and opened by the study physician once each patientwas enrolled into the trial after meeting the inclusion and exclusion criteria. Patients wereenrolled in the order they presented and the sealed envelopes were opened in strictnumerical sequence. Masking was not possible because of the different formulations andways of giving the two drugs. Procedures Each enrolled patient was randomly assigned to treatment with either gatifloxacin tablets(400 mg) 10 mg per kg per day in a single oral dose for 7 days or chloramphenicol capsules(250 mg or 500 mg) 75 mg per kg per day in four divided oral doses for 14 days.Gatifloxacin tablets were cut and weighed and the patients' daily doses were prepared insealed plastic bags. The per-protocol planned duration of chloramphenicol treatment of 14days was modified for blood-culture-negative patients, who received at least 8 days of chloramphenicol and stopped either on day 8 or 5 days after being afebrile, whichever camelater. Gatifloxacin was given for 7 days in all patients.After enrolment, patients were managed as outpatients and seen by trained communitymedical auxiliaries (CMAs), as described previously. The CMAs made a visit to eachpatient's house every 12 h for either 10 days (gatifloxacin group), 14 days (chloramphenicolgroup), or until the patient was cured. The CMA directly observed each patient ingesting thesingle dose of gatifloxacin and two doses of chloramphenicol. The physicians re-examinedthe patients on days 8 and 15, and at 1, 3, and 6 months. All examinations were standardisedand entered into case record forms.Complete blood counts were done on days 1, 8, and 15. On day 1, serum creatinine,bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were alsochecked. Random plasma glucose was measured on day 1, day 8, day 15, and 1 month. Ondays 2–7, during the evening visit, the blood glucose was measured by finger-prick testing(OneTouch SureStep, Johnson and Johnson, USA) by the CMAs. Haemoglobin A 1C  wasmeasured at 3 months. Arjyal et al.Page 3Published as:  Lancet Infect Dis . 2011 June ; 11(6): 445–454.  S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t    Blood culture was done as described previously in all patients at admission, in the culture-positive patients on day 8, and if symptoms and signs suggested further infection.Stool cultures were done on admission in all patients, and in culture-positive patients aftercompletion of treatment and at the 1 month, 3 month, and 6 month visits in 10 mL of Selenite F broth and incubated at 37°C. After the overnight incubation, the broth wassubcultured onto MacConkey agar and xylose lysine decarboxylase agar media.Isolates were screened using standard biochemical tests, and S typhi  and S paratyphi  A wereidentified using API20E (BioMerieux, Paris, France) and slide agglutination with specificantisera (MurexBiotech, Dartford, UK).Minimum inhibitory concentrations (MICs) were calculated for amoxicillin, azithromycin,chloramphenicol, co-trimoxazole, nalidixic acid, ofloxacin, ciprofloxacin, tetracycline,gatifloxacin, and ceftriaxone by E-test (AB Biodisk, Solna, Sweden).The primary endpoint of this study was the composite endpoint of treatment failure, whichconsisted of any one of the following: persistence of fever of more than 37·5°C at day 10 of treatment; the need for rescue treatment with ceftriaxone or ofloxacin as judged by thetreating physician; microbiological failure, defined as a positive blood culture for S typhi  or S paratyphi  A on day 8; relapse, that is reappearance of culture-confirmed (includingmismatch of serotypes [eg, day 1 blood culture positive for S typhi  and relapse blood culturepositive for S paratyphi  A or vice versa]) or syndromic enteric fever on or after day 11 today 31 in patients who were initially categorised as successfully treated; and occurrence of enteric-fever-related complications. Time to treatment failure was defined as the time fromthe first dose of treatment until the date of the earliest failure event of that patient, andpatients without an event were censored at the date of their last follow-up visit.Secondary endpoints were fever clearance time (FCT: time from the first dose of treatmentgiven until the temperature was  37·5°C and the patient remained afebrile for at least 48 h);time to relapse until day 31, day 62, or month 6 of follow-up; and faecal carriage at thefollow-up visits at 1, 3, and 6 months. The patients' FCTs were calculated electronically onthe basis of twice-daily recorded temperatures. Patients without recorded fever clearance orrelapse were censored at the date of their last follow-up visit. To reduce possible bias, aninvestigator not involved in the recruitment of patients decided patients' final outcomes byuse of a masked database. Statistical analysis The trial was designed as a superiority trial with the hypothesis that gatifloxacin wassuperior to chloramphenicol in patients with enteric fever. The sample size was calculated todetect a difference of 10% between the two groups in the proportion of patients reachingtreatment failure at the two-sided 5% significance level with 80% power. We assumedtreatment failure rates of 15% in the chloramphenicol and 5% in the gatifloxacin group,leading to a total required sample size of 160 patients with culture-confirmed enteric feverper group—320 patients in total. On the basis of results from a previous study, we assumedthat about 40% of patients who were randomly assigned treatment had culture-confirmedenteric fever. To allow for a loss to follow-up rate of about 5%, a total of 853 patients withsuspected enteric fever were recruited to the trial.Times to treatment failure, fever clearance, and relapse, were analysed by use of survivalmethods. The cumulative incidence of events was calculated with the Kaplan-Meier method,and comparisons were based on Cox regression models with the treatment group as the onlycovariate. For the primary endpoint (treatment failure), we also compared the absolute risk  Arjyal et al.Page 4Published as:  Lancet Infect Dis . 2011 June ; 11(6): 445–454.  S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t    of treatment failure until day 31 on the basis of Kaplan-Meier estimates and standard errorsaccording to Greenwood's formula. Additionally, the time to treatment failure was analysedin the subgroups defined by culture result, pathogen ( S typhi  or S paratyphi  A), and age (<16years or  16 years), and heterogeneity of the treatment effect was tested with a Coxregression model that included an interaction between treatment and subgroup.The per-protocol analysis population consisted of all patients with blood-culture-confirmedenteric fever. We also analysed all patients who were assigned treatment, with the exceptionof those patients who were mistakenly randomised or withdrew before the first dose of studytreatment, for treatment failure and safety.All reported tests were done at the two-sided 5% significance level, and 95% CIs arereported. All analyses were done with the statistical software R version 2.9.1.The trial is registered on controlled-trials.com, number ISRCTN 53258327. Role of the funding source The sponsor of the study had no role in study design, data collection, data analysis, datainterpretation, or writing of the report. The corresponding author had full access to all thedata in the study and had final responsibility for the decision to submit for publication. Results Of 1151 patients assessed, 853 were assigned treatment; 844 were analysed, 418 assignedchloramphenicol and 426 gatifloxacin (figure 1). The baseline characteristics of the patientswere similar in the two treatment groups (table 1). The proportion of patients with treatmentfailure was similar in the two treatment groups in patients with culture-positive disease(table 2). Of the five patients with persistent fever on day 10 in the gatifloxacin group (table2), two became afebrile on day 11 and did not require rescue treatment. The other threepatients were effectively treated with intravenous ceftriaxone 50 mg/kg per day in a singledose for 7 days. The five patients in the chloramphenicol group who needed rescuetreatment were successfully treated with ofloxacin 20 mg/kg per day in two divided dosesper day for 7 days. In all cases, rescue treatment was initiated on either day 10 or day 11.Two patients with microbiological failure in the gatifloxacin group also had persistent fever,and responded well to ceftriaxone 50 mg/kg per day in a single daily dose for 7 days. Allrelapse patients, consisting of seven (five of whom were culture confirmed) in thechloramphenicol group and four (three of whom were culture confirmed) in the gatifloxacingroup, were also treated with ofloxacin 20 mg/kg per day, and recovered.The secondary outcome measures, which included fever clearance time (median 3·95 days inthe chloramphenicol group and 3·90 in the gatifloxacin group) and time to relapse until day31 or day 62 also showed no significant difference between the groups (table 2). Onlysyndromic relapses were documented between day 62 and 6 months. Figure 2 shows theKaplan-Meier estimates for the time to treatment failure, fever clearance, and relapse.Stool samples at baseline were positive for S typhi  or S paratyphi  A in 16 (10%) of 157patients in the chloramphenicol group and 14 (9%) of 160 patients in the gatifloxacin group.The proportion of positive stool samples at 1–6 months of follow-up was low in bothgroups: at 1 month, only three (2%) of 148 and none of 154 patients were stool-culture-positive in the chloramphenicol and gatifloxacin groups (p=0·12), respectively. At the end of 3 months, only one patient (in the chloramphenicol group) had a positive stool culture, andat 6 months no patients had a positive stool culture. Arjyal et al.Page 5Published as:  Lancet Infect Dis . 2011 June ; 11(6): 445–454.  S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t   S  p on s  or  e d D  o c  um en t  
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