SummaryBackgroundBecause treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever.MethodsWe did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2–13 years) and adult (aged 14–45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2–13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed.FindingsBetween Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55–1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08–0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71–32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported.InterpretationOur results suggest that fluoroquinolo...

INTRODUCTION: Drug resistant Salmonella spp. is endemic in several Asian countries. Nalidixic acid-resistant Salmonella enterica serovar Typhi and Salmonella enterica serovar Paratyphi A show reduced susceptibility to fluoroquinolones and have resulted in a rise in treatment failures. Over the past few decades, nalidixic acid-resistant Salmonella spp have emerged in Nepal as well.MATERIAL & METHODS: This is a retrospective study that aims to provide a more recent antibiogram of S. Typhi and S. Paratyphi A isolates in Kathmandu. Between Poush, 2071 and Ashwin, 2072 (December 16, 2014 to October 17, 2015), 186 culture positive cases of enteric fever were diagnosed at the Civil Service Hospital. Upon isolation of S. Typhi or S. Paratyphi A, antimicrobial susceptibility testing was performed with amoxicillin, azithromycin, ceftriaxone, chloramphenicol, ciprofloxacin, cotrimoxazole, nalidixic acid, ofloxacin and tetracyciline.RESULTS: This study shows a much higher frequency of nalidixic acid-resistance in Kathmandu than previously reported; 95.7% in Salmonella enterica serovar Paratyphi A and 86.5% in Salmonella enterica serovar Typhi.The rates of ciprofloxacinand ofloxacin-resistance were over 50% in both serovar.CONCLUSION: In Nepal, it is necessary to reevaluate the use of fluoroquinolone therapy and introduce feasible alternatives so as to curb treatment failures.Journal of Universal College of Medical Sciences (2017) Vol. 5, No, 2, Page: 22-25

Background Azithromycin and trimethoprim-sulfamethoxazole (SXT) are widely used to treat undifferentiated febrile illness (UFI). We hypothesized that azithromycin is superior to SXT for UFI treatment, but the drugs are non-inferior to each other for culture-confirmed enteric fever treatment. Methods We conducted a double blind, randomized, placebo-controlled trial of azithromycin (20 mg/kg/day) or SXT (trimethoprim 10 mg/kg/day + sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients (aged 3-64 years) presenting to two Kathmandu hospitals with temperature ≥ 38.0°C for ≥4 days without localising signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events. ClinicalTrials.gov number: NCT02773407. Results From June 2016 to May 2019, we randomized 326 participants (163 in each arm); 87 (26.7%) had blood culture-confirmed enteric fever. In all participants, the median FCT was 2.7 days (95% CI 2.6-3.3) in the SXT arm and 2.1 days (95% CI 1.6-3.2) in the azithromycin arm 1.25 (95% CI 0.99-1.58, P=0.059). The hazard ratio of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI 0.37-1.05, p=0.073). Planned sub-group analysis showed azithromycin resulted in faster FCT in those with sterile blood cultures and less relapses in culture-confirmed enteric fever. Nausea, vomiting, constipation, and headache were more common in the SXT arm. Conclusions Despite similar FCT and treatment failure in the two arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal.

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia.  A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)

Background: Enteric fever is a significant cause of morbidity in Nepal. In the past, Salmonella entericaserovar Typhi (S. Typhi) was the major causative organism of enteric fever. However, more recently, Salmonella entericaserovar Paratyphi (S.Paratyphi) A has been isolated from most patients presenting with enteric fever in various regions of Nepal. This study aimed to evaluate age differences in patients presenting with typhoid and paratyphoid fever.Materials & Methods: Between December 2014 and October 2015, 186 patients presented with enteric fever to the Civil Service Hospital in Kathmandu. S. Typhi and S.Paratyphi A were isolated from blood cultures in 48.4% and 51.6% of the cases, respectively. Age groups of the patients infected with either serovar were compared.Results: The mean age of patients from whom S. Typhi was isolated was 19.3 years, while the mean age of patients from whom S. Paratyphi A was isolated was 25.2 years; p=0.025.Conclusion: Our study shows that age is an important factor in having either typhoid or paratyphoid fever. This will help in the prevention of typhoid and paratyphoid fever in various age groups.Journal of Nobel Medical CollegeVolume 6, Number 2, Issue 11 (July-December, 2017) Page:25-28