Typhoid Fever: Combined vs. Single Antibiotic Therapy

Sheba Medical Center

Status and phase: Unknown; Phase 4

Conditions: Typhoid Fever

Treatments: Drug: ceftriaxone; Drug: ceftriaxone and azithromycin; Drug: azithromycin and cefixime; Drug: azithromycin

Study type: Interventional

Funder types: Other

Identifiers

NCT02224040

64/12

Details and patient eligibility

About

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.

Full 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.

Enrollment: 120 estimated patients

Sex: All

Ages: 2 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

120 participants in 4 patient groups

Ceftriaxone I.V

Experimental group

Description:

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).

Treatment:

Drug: ceftriaxone

Ceftriaxone I.V+Azithromycin P.O

Experimental group

Description:

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).

Treatment:

Drug: ceftriaxone and azithromycin

Azithromycin P.O

Experimental group

Description:

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.

Treatment:

Drug: azithromycin

Azithromycin P.O+Cefixime P.O

Experimental group

Description:

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.

Treatment:

Drug: azithromycin and cefixime