Main drugs

• Fluoroquinolones: Park's Textbook of Preventive and Social Medicine calls these the traditional drug of choice for typhoid. They are inexpensive, well tolerated and work faster than the older drugs. The textbook gives ciprofloxacin or ofloxacin at about 15 mg/kg/day for 5-7 days in fully sensitive cases. Resistance is now widespread, though. The CDC says about 80% of US Salmonella Typhi isolates are resistant or have reduced susceptibility to ciprofloxacin.
• Older drugs: Chloramphenicol, amoxicillin and TMP-SMX still work only if the strain is fully sensitive. They need 14-21 days and are now rarely first choice.
• Azithromycin and ceftriaxone: Tintinalli's Emergency Medicine lists fluoroquinolones, cephalosporins (cefixime, ceftriaxone) and azithromycin as current options. It notes that fluoroquinolone resistance is rising, especially in travelers returning from South and Southeast Asia.
• XDR typhoid: Since 2016, Pakistan has had a large outbreak of XDR S. Typhi. It is resistant to ampicillin, chloramphenicol, ceftriaxone, ciprofloxacin and TMP-SMX. It remains susceptible only to azithromycin and carbapenems (Red Book 2021).
• Empiric treatment (CDC): For a patient who has been to Pakistan or Iraq, or who has not traveled abroad, the CDC Yellow Book advises azithromycin for uncomplicated illness. It advises a carbapenem for complicated illness. Ceftriaxone and azithromycin remain appropriate for travelers returning from most other countries.

Other points

• Severe, toxic patients: Park's notes that hydrocortisone 100 mg daily for 3-4 days may be given.
• Supportive care: Fluids, fever control, nutrition and rest. Treatment is adjusted once blood culture susceptibility results are back.
• Chronic carriers: Park's describes ampicillin or amoxicillin (4-6 g/day) with probenecid for 6 weeks. Cholecystectomy is sometimes needed.
• Recent evidence: A 2026 systematic review of azithromycin versus ceftriaxone in children with uncomplicated typhoid (PMID 42928111) compares these two options. I only saw the title, not the findings, so I can't say what it concluded. A 2024 systematic review (PMID 39623850) looked at oral azithromycin against other antibiotics. I did not check whether either changes the textbook advice above.

Prevention

Current guidance

• Base empiric treatment on travel history. The CDC Yellow Book advises azithromycin for uncomplicated illness and a carbapenem for complicated illness in two groups: patients who traveled to Pakistan or Iraq, and patients who did not travel internationally.
• Ceftriaxone and azithromycin remain appropriate empiric options for travelers returning from most other countries.
• Adjust treatment once susceptibility results return.
• Some patients with extensively drug-resistant (XDR) typhoid do not improve on a carbapenem alone. Case reports suggest adding a second drug such as azithromycin may help.
• Ceftriaxone resistance has also been found in isolates from travelers returning from Iraq, India and Afghanistan.
• Azithromycin resistance has been found in Bangladesh, Cambodia, India, Nepal, Pakistan, Saudi Arabia and the US.

• A 2026 Lancet Infectious Diseases trial states that WHO recommends azithromycin for uncomplicated typhoid fever. The same trial says both azithromycin and cefixime have reported failure rates of 10% or more.
• WHO also recommends typhoid conjugate vaccines, alongside water, sanitation and food safety measures. This is in a 2026 Weekly Epidemiological Record, which I only skimmed.

• Uncomplicated cases can be treated as outpatients. Options listed are azithromycin 20 mg/kg/day for 7 days (maximum 1 g/day), cotrimoxazole 960 mg twice daily for 2 weeks, or cefixime 20 mg/kg/day for 10-14 days.
• Severe cases get ceftriaxone, with a switch to an oral drug once the patient improves and a total course of 10-14 days.
• Blood culture is the gold standard, and the Widal test should be avoided for diagnosis.
• Empiric fluoroquinolones should be avoided, and so should empiric carbapenems.

Recent evidence

• ACT-South Asia trial, 2026 (PMID 42624818): This randomized trial enrolled 1847 patients aged 2-65 in Nepal, Bangladesh and Pakistan. Azithromycin plus cefixime was no better than azithromycin alone, with treatment failure in 5.1% of patients in each group. The authors concluded that this supports WHO's advice of azithromycin alone for uncomplicated typhoid.
• Azithromycin versus ceftriaxone in children, 2026 meta-analysis (PMID 42928111): Six trials with 492 children found similar clinical cure (RR 0.98, 95% CI 0.93-1.03). Azithromycin had fewer relapses, but the certainty of that finding was low and all trials were open-label.
• Parry et al., 2023 review (PMID 37274536): Systematic reviews of randomized trials show no significant difference in efficacy between the common antibiotics. Resistance has been described to every antimicrobial, so the choice should follow local resistance patterns and national guidance. XDR isolates need azithromycin and/or meropenem. Evidence for treating chronic fecal carriers is poor.
• Oral drug limits in XDR typhoid, 2026 review (PMID 42841931): This review looks at the pharmacokinetic and pharmacodynamic limits of existing oral antibiotics in XDR typhoid. I only saw the title.
• Lancet seminar on enteric fever, 2025 (Kuehn et al., Lancet 2025;406:1283-94): It appeared in a reference list and I did not read it. It is probably the most current expert overview, so it is worth opening.

How the guidance fits together

• Treatment follows where the infection was acquired and local susceptibility, not one fixed drug.
• Azithromycin is now the main oral choice for uncomplicated disease.
• Ceftriaxone is used for severe disease or for travelers from areas without XDR strains.
• Carbapenems (meropenem) are kept for complicated or XDR infection.
• Fluoroquinolones are no longer recommended empirically, because resistance is common.

What I couldn't confirm