Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia: a randomised controlled trial protocol

Abstract

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)

The rapid emergence ofSalmonellaTyphi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi

“…One AMU policy that could be modified is to increase the dose of ciprofloxacin given, to achieve a “mutant prevention concentration”, although this has not shown promise in the limited empirical studies carried out thus far (Fantin et al 2009). Another antimicrobial usage policy that could be considered is a switch to combination therapy for suspected typhoid fever (Zmora et al 2018; Giri et al 2021), although without improved diagnostics this might just serve to increase the overall antibiotic pressure.…”

Comparison of Culture Proven Enteric Fever Treatment with Meropenem Alone Vs Combination of Meropenem and Azithromycin

“…This supports Current study observation that the combination therapy does not significantly enhance the effectiveness of treatment compared to Meropenem alone. Contrastingly, a study by Giri. et al (2021) reported that the combination of Azithromycin with other antibiotics led to a quicker resolution of symptoms and a shorter hospital stay (22).…”

“…Contrastingly, a study by Giri. et al (2021) reported that the combination of Azithromycin with other antibiotics led to a quicker resolution of symptoms and a shorter hospital stay (22). Their findings suggested that Azithromycin could play a vital role in enhancing the effectiveness of the treatment for enteric fever (23,24).…”

Scope of antibiotic stewardship in enteric fever: An evidence-based summary

“…6 A Phase IV, international, multicentre randomised controlled trial is currently in progress in South Asia evaluating this combination. 7…”