Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults

Niv Zmora, Sudeep Shrestha, Ami Neuberger, Yael Paran, Rajendra Tamrakar, Ashish Shrestha, Surendra K Madhup, T R S Bedi, Rajendra Koju, Eli Schwartz, Niv Zmora, Sudeep Shrestha, Ami Neuberger, Yael Paran, Rajendra Tamrakar, Ashish Shrestha, Surendra K Madhup, T R S Bedi, Rajendra Koju, Eli Schwartz

Abstract

Background: Emerging resistance to antibiotics renders therapy of Typhoid Fever (TF) increasingly challenging. The current single-drug regimens exhibit prolonged fever clearance time (FCT), imposing a great burden on both patients and health systems, and potentially contributing to the development of antibiotic resistance and the chronic carriage of the pathogens. The aim of our study was to assess the efficacy of combining third-generation cephalosporin therapy with azithromycin on the outcomes of TF in patients living in an endemic region.

Methods: An open-label, comparative trial was conducted at Dhulikhel Hospital, Nepal, between October 2012 and October 2014. Only culture-confirmed TF cases were eligible. Patients were alternately allocated to one of four study arms: hospitalized patients received either intravenous ceftriaxone or a combination of ceftriaxone and oral azithromycin, while outpatients received either oral azithromycin or a combination of oral azithromycin and cefexime. The primary outcome evaluated was FCT and the secondary outcomes included duration of bacteremia.

Results: 105 blood culture-confirmed patients, of whom 51 were treated as outpatients, were eligible for the study. Of the 88 patients who met the inclusion criteria for FCT analysis 41 patients received a single-agent regimen, while 47 patients received a combined regimen. Results showed that FCT was significantly shorter for the latter (95 versus 88 hours, respectively, p = 0·004), and this effect was exhibited in both the hospitalized and the outpatient sub-groups. Repeat blood cultures, drawn on day 3, were positive for 8/47 (17%) patients after monotherapy, versus 2/51 (4%) after combination therapy (p = 0·045). No severe complications or fatalities occurred in any of the groups.

Conclusions: Combined therapy of third-generation cephalosporins and azithromycin for TF may surpass monotherapy in terms of FCT and time to elimination of bacteremia.

Trial registration: Trial registration number: NCT02224040.

Conflict of interest statement

The study was funded by two sources, Dhulikhel Hospital, Kathmandu University Hospital, Dhulikhel, Nepal and by The Chaim Sheba Medical Center, Tel Hashomer, Israel. The authors have declared that no competing interests exist.

Figures

Fig 1. Study flow diagram of patients…
Fig 1. Study flow diagram of patients with blood cultures positive for S. Typhi and S. Paratyphi.
Fig 2
Fig 2
Kaplan-Meir curve of fever clearance time (FCT) in dual antibiotic therapy versus monotherapy. A. Time to defervescence for the outpatient study arms; B. Time to defervescence for the inpatient study arms; C. Time to defervescence for the two study arms receiving monotherapy versus the two study arms receiving dual therapy. Dashed lines represent monotherapy, continuous lines represents dual therapy.

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