Typhoid Fever: Combined vs. Single Antibiotic Therapy

NCT ID: NCT02224040

Last Updated: 2014-08-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2015-08-31

Brief Summary

The current study goal is to examine the effect of Cephalosporins, Azithromycin and the combination of both on typhoid fever therapy in endemic population.

The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove superior to each drug, ceftriaxone or azithromycin, alone.

Detailed Description

Typhoid Fever is a highly prevalent infection in the Indian subcontinent. Due to multidrug resistant strains in these areas, third generation cephalosporins, such as ceftriaxone, are the treatment of choice. However, the latter regimen exhibits a slow response with mean time of 5 to 7 days or even longer to defervescence, which could be attributed to poor penetration capability of the drug into cells, and thus difficulty to eradicate the bacteria from the intracellular niche.

Attempts have been made to overcome this setback by introducing alternative antibiotic regimens, such as azithromycin. However studies comparing between azithromycin and a third-generation cephalosporin for the treatment of typhoid fever in adult population in the Indian subcontinent are lacking.

Over the last few years our approach towards non-immunized travelers, who acquired typhoid fever in the Indian subcontinent, was to administer a combination therapy of intravenous ceftriaxone with oral azithromycin. The rationale of this dual regimen was its pharmacokinetic profile, which suggests a complimentary action of the two agents - ceftriaxone on the extracellular compartment and azithromycin on the intracellular compartment. Moreover, in our clinical experience, preliminary published data has proven combination therapy significantly superior to ceftriaxone alone albeit in a small group of travelers.

In the current study the investigators intend to compare the efficacy of ceftriaxone vs. azithromycin and vs. combined therapy of both agents for the treatment of uncomplicated typhoid fever in terms of time to defervescence.

4 different treatment strategies will be examined (as mentioned in the arm section). All participants will be checked for vital signs, will undergo physical examination, ECG, laboratory testing, blood, urine and stool culture and tests for susceptibility to antibiotics.

Conditions

Typhoid Fever

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ceftriaxone I.V

The participants in this arm will receive the following drug and dosage: adult: Ceftriaxone intravenous 2 gr once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day (maximum dose 2.5 g/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).

Group Type: EXPERIMENTAL

ceftriaxone

Intervention Type: DRUG

Ceftriaxone I.V+Azithromycin P.O

The participants in this arm will receive the following drugs and dosages: adult: 2 g intravenous ceftriaxone and 500 mg oral azithromycin once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day and oral 20 mg/kg azithromycin suspension once a day. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).

Group Type: EXPERIMENTAL

ceftriaxone and azithromycin

Intervention Type: DRUG

Azithromycin P.O

The participants in this arm will receive the following drug and dosage: adult: azithromycin oral 500 mg once a day. Pediatric: oral 20 mg/kg azithromycin suspension once a day (maximum dose 1000 mg/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.

Group Type: EXPERIMENTAL

azithromycin

Intervention Type: DRUG

Azithromycin P.O+Cefixime P.O

The participants in this arm will receive the following drugs and dosages: adult: 500 mg azithromycin and 400 mg cefixime. Pediatric: oral 20 mg/kg azithromycin suspension once a day and oral 10 mg/kg cefixime. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.

Group Type: EXPERIMENTAL

azithromycin and cefixime

Intervention Type: DRUG

Interventions

ceftriaxone

Intervention Type: DRUG

ceftriaxone and azithromycin

Intervention Type: DRUG

azithromycin

Intervention Type: DRUG

azithromycin and cefixime

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Blood culture-proven typhoid fever (S. typhi or S. paratyphi)
• Signed informed consent to participate in the study.

Exclusion Criteria

• Allergy to ceftriaxone or macrolides
• Major typhoid fever-associated complications
• Inability to swallow oral medication
• Underlying illness
• Pregnancy
• Lactation
• Treatment within the past 4 days with an antibiotic that may be effective against typhoid fever

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Prof. Eli Schwartz MD, DTMH

Principal Investigator of the geographic clinical

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eli Schwartz, MD, DTMH

Role: PRINCIPAL_INVESTIGATOR

Sheba Medical Center

Locations

Dhulikhel hospital

Dhulikhel, , Nepal

Site Status: RECRUITING

Countries

Nepal

Central Contacts

Eli Schwartz, MD, DTMH

Role: CONTACT

Eli.schwartz@sheba.health.gov.il

+97235308456

Facility Contacts

Sudeep Shrestha, M.D

Role: primary

itsactionpotential@gmail.com

References

Zmora N, Shrestha S, Neuberger A, Paran Y, Tamrakar R, Shrestha A, Madhup SK, Bedi TRS, Koju R, Schwartz E. Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults. PLoS Negl Trop Dis. 2018 Apr 23;12(4):e0006380. doi: 10.1371/journal.pntd.0006380. eCollection 2018 Apr.

Reference Type: DERIVED

PMID: 29684022 (View on PubMed)

Other Identifiers

64/12

Identifier Type: -

Identifier Source: org_study_id