What is the recommended treatment for enteric fever?

Treatment of Enteric Fever

For enteric fever, azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7 days is the recommended first-line treatment in areas with high fluoroquinolone resistance, while ceftriaxone 50-80 mg/kg/day (maximum 2g/day) intravenously for 5-7 days should be used for severe cases requiring hospitalization. 1, 2

Initial Diagnostic Approach

• Always obtain blood cultures before initiating antibiotics whenever possible to confirm the diagnosis and guide antimicrobial therapy 1, 2
• Consider enteric fever in any febrile patient with travel history to endemic areas (South and Southeast Asia, Central and South America, Africa), consumption of foods prepared by people with recent endemic exposure, or laboratory exposure to Salmonella typhi or Paratyphi 3
• For patients presenting with clinical features of sepsis, initiate broad-spectrum antimicrobial therapy immediately after blood culture collection, then narrow therapy based on susceptibility results 1, 2

First-Line Treatment Selection Based on Clinical Severity

Mild to Moderate Cases (Outpatient or Non-Severe)

• Azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7 days is the preferred first-line therapy, particularly in regions with high fluoroquinolone resistance 1, 2
• Azithromycin demonstrates a 94% cure rate in children with typhoid fever and significantly lower risk of relapse (OR 0.09) compared to ceftriaxone 1
• This agent also shows lower risk of clinical failure (OR 0.48) and shorter hospital stays compared to fluoroquinolones in systematic reviews 1

Severe Cases Requiring Hospitalization

• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) intravenously for 5-7 days is the first-line therapy for hospitalized patients 1, 2
• For adults, ceftriaxone 1-2g every 12-24 hours is appropriate based on severity 2
• Patients treated initially with parenteral antibiotics should be transferred to an oral regimen (such as azithromycin) once clinical improvement occurs and temperature has been normal for 24 hours 1, 2

Alternative Treatment Options Based on Susceptibility

When Fluoroquinolone Susceptibility is Confirmed

• Avoid using fluoroquinolones empirically for cases originating from South Asia due to high resistance rates (over 70% of S. typhi isolates in many regions are now resistant) 1, 2
• For fully susceptible strains, ciprofloxacin or ofloxacin may be used, but this should only be considered after susceptibility testing confirms sensitivity 1, 4
• The FDA-approved indication for ciprofloxacin includes typhoid fever (enteric fever) caused by Salmonella typhi, though efficacy in eradicating the chronic carrier state has not been demonstrated 4
• Critical caveat: An ofloxacin MIC of ≥0.25 µg/mL, or the presence of nalidixic acid resistance, defines S. typhi infections in which response to fluoroquinolones may be impaired, with treatment success dropping from 96% (MIC ≤0.125 µg/mL) to 53% (MIC 1.00 µg/mL) 5

Oral Cephalosporin Option

• Cefixime 8 mg/kg/day as a single daily dose (400 mg for adults) for 7-14 days is an appropriate oral option, particularly in children over 28 days old 1
• However, cefixime may not perform as well as fluoroquinolones or azithromycin, with studies showing increased clinical failure (RR 13.39), microbiological failure (RR 4.07), and relapse (RR 4.45) compared to fluoroquinolones 6
• Time to defervescence with cefixime may be 1.74 days longer compared to fluoroquinolones 6

Treatment Duration and Monitoring

• Most patients with uncomplicated enteric fever should receive 7 days of appropriate antibiotics 1, 2
• For ceftriaxone, 5-7 days is the recommended duration 1, 2
• Expected fever clearance should occur within 4-5 days of appropriate therapy 1
• Monitor for clinical response and consider modifying therapy when susceptibility testing results become available 1, 2

Special Populations

Infants Under 3 Months

• Treat with a third-generation cephalosporin (ceftriaxone) 1

Pediatric Patients (1-17 Years)

• Ciprofloxacin is FDA-approved for complicated urinary tract infections and inhalational anthrax in pediatric patients, but is not a drug of first choice in the pediatric population for enteric fever due to increased incidence of adverse events related to joints and surrounding tissues 4
• Azithromycin or ceftriaxone are preferred options in children 1, 2

Comparative Effectiveness: Key Evidence

Azithromycin vs. Ceftriaxone

• Ceftriaxone may result in decreased clinical failure compared to azithromycin (RR 0.42), though the evidence is of low certainty 6
• Time to defervescence may be 0.52 days shorter with ceftriaxone compared to azithromycin 6
• However, relapse may be higher with ceftriaxone (RR 10.05), though this evidence is very low certainty 6

Fluoroquinolones vs. Azithromycin in Resistant Settings

• In populations with both multidrug resistance (MDR) and nalidixic acid resistance (NaR), ofloxacin had higher rates of clinical failures compared to azithromycin (RR 2.20) in Vietnam studies from 1998-2002 7
• More recent evidence from Vietnam (2004-05) showed no difference between the newer fluoroquinolone gatifloxacin and azithromycin, with both performing well 7

Critical Pitfalls to Avoid

• Do not use ciprofloxacin empirically for cases from South Asia where fluoroquinolone resistance exceeds 70% 1, 2
• Do not rely solely on clinical presentation for diagnosis—obtain cultures whenever possible to guide therapy and detect resistance 1, 2
• Avoid premature discontinuation of antibiotics before complete resolution of symptoms 2
• Consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 1, 2
• Resistance to fluoroquinolones is essentially a class effect and is increasing globally 1

Rehydration and Supportive Care

• Evaluate all patients for dehydration, which increases risk of life-threatening illness and death, especially in young children and older adults 3
• Isotonic intravenous fluids are recommended for severe dehydration 2
• Reassess fluid and electrolyte balance in patients with persistent symptoms 1

Monitoring for Complications

• For patients with persistent or recurrent signs of peritoneal irritation, failure of bowel function to return to normal, continued fever or leukocytosis, consider CT imaging to identify persistent or new intra-abdominal infection 2