Typhoid Fever

Typhoid fever (and the related paratyphoid fever) — together often called enteric fever — is a systemic bacterial infection caused by Salmonella enterica serotype Typhi (typhoid) or serotypes Paratyphi A, B, or C (paratyphoid), transmitted exclusively human-to-human through food or water contaminated by the feces or urine of an acutely infected person, a convalescent, or an asymptomatic chronic carrier — humans are the only reservoir.^[1] For Canadian travellers, risk is concentrated in South Asia (Bangladesh, India, Nepal, Pakistan, and neighbouring countries), where the Committee to Advise on Tropical Medicine and Travel (CATMAT) estimates risk at roughly 1 in 3,000 travellers, versus roughly 1 in 50,000-100,000 for intermediate-risk destinations and under 1 in 300,000 for low-risk destinations.^[2]

Two licensed vaccines — oral live-attenuated Ty21a and injectable Vi polysaccharide — reduce but do not come close to eliminating risk (roughly 50% efficacy for both), and neither reliably protects against paratyphoid fever, so food and water safety precautions remain essential for every traveller regardless of vaccination status.^[2][1] Once infection is confirmed or strongly suspected, treatment selection has a genuinely current, high-stakes twist: fluoroquinolones — the older first-line teaching — are no longer reliable empiric therapy for infection acquired in South Asia, where well over 99% of isolates now show decreased ciprofloxacin susceptibility; azithromycin or ceftriaxone are the correct current empiric choices in that setting.^[1][3] A small proportion of infected individuals — roughly 1-4% — become long-term asymptomatic biliary carriers, a distinct public-health consideration with real food-handler and occupational implications, including in Canada.^[1][4]

Typical presentation

Onset is classically insidious: fatigue and a fever that increases gradually day over day, typically reaching 39-40°C by day 3-4, with a lower morning trough and a higher evening peak — the "stepwise" fever pattern often described in textbooks.^[1] Headache, anorexia, and malaise are nearly universal; abdominal pain is common, with constipation more typical in adults and diarrhea more typical in children.^[1] Hepatosplenomegaly is often detectable on examination, and dry cough, myalgia, and sore throat are also reported.^[1] Incubation is typically 6-30 days (most commonly 8-14 days) after ingestion of contaminated food or water; untreated illness lasts approximately a month.^[1]

2 classic signs worth knowing honestly, not just by name

Paratyphoid fever — clinically similar, epidemiologically distinct, and not reliably vaccine-preventable

Salmonella Paratyphi A causes a presentation essentially indistinguishable from typhoid at the bedside, but its epidemiology is shifting in a way that matters for counselling: it now accounts for up to roughly 35% of enteric fever in India and Nepal and over 60% in China, and its relative contribution to overall enteric fever incidence in South Asia is rising.^[3] Neither licensed typhoid vaccine reliably protects against Paratyphi A; limited trial data suggest Ty21a may offer some cross-protection against Paratyphi B specifically, but this is not considered reliable enough to base counselling on, and there is no equivalent suggestion of cross-protection against Paratyphi A.^[2]

• Travel to South Asia (Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka) without vaccination — the highest-risk destination group for Canadian travellers, at roughly 1 in 3,000 travellers.^[2]
• Visiting friends and relatives (VFR travel) — disproportionately affected due to longer stays, residing in family homes rather than tourist accommodation, and typically less cautious food/water behaviour, similar to the VFR risk pattern seen in malaria.^[2]
• Extended-duration travel, which prolongs cumulative exposure to potentially contaminated food and water even outside South Asia.^[2]
• Travel to other endemic regions — sub-Saharan Africa, Southeast Asia, and parts of Latin America — which carries intermediate-to-low average risk but should still prompt individualized counselling in the presence of other risk factors above.^[2]
• Consuming raw produce, street food, tap water, or ice made from untreated water in an endemic area.
• Assuming vaccination alone is sufficient protection and relaxing food/water precautions as a result — neither licensed vaccine is close to fully protective.^[1]
• Ongoing exposure to a known or unrecognized chronic carrier — the Ottawa, Canada outbreak (2018-2022) demonstrated that this risk is not purely a travel-medicine issue: 7 locally acquired cases over nearly 4 years were traced to a single asymptomatic food-handler carrier who had likely acquired the infection before immigrating to Canada.^[4]
• Unknown vaccination status combined with a false sense of protection from a remembered childhood vaccination — Ty21a and Vi polysaccharide protection both wane over years and require destination-appropriate revaccination for repeat travel (see Choose Initial Treatment).

Blood culture — the diagnostic gold standard, with a genuine sensitivity limitation

Blood culture remains the reference standard for diagnosis, but a single culture is positive in only approximately 50% of true cases — a limitation that pharmacists should understand honestly rather than treat blood culture as a perfectly sensitive test.^[1] Sensitivity is reduced further by prior antibiotic exposure (common in a patient who self-medicated abroad or received empiric treatment before the culture was drawn) and by low blood-volume sampling; larger blood volumes and repeat cultures both improve diagnostic yield, and cultures may need up to 7 days of incubation before a negative result can be reported with confidence.^[1]

Other diagnostic tests

Bone marrow culture is substantially more sensitive — approximately 80% — and, importantly, its sensitivity is not reduced by recent antibiotic exposure, making it a genuinely useful option when blood culture is negative but clinical suspicion remains high, though its invasiveness means it is reserved for that specific scenario rather than used routinely.^[1] Stool and urine cultures are less sensitive than blood culture during the first week of illness but become more useful later in the illness course and are the basis for chronic-carrier detection (see Monitoring & Follow-Up).^[1] The Widal serologic test, which measures antibody titres, is unreliable — it cannot distinguish acute infection from past infection or prior vaccination — but remains widely used in low-resource endemic settings because of its low cost; a traveller who returns with only a positive Widal result from abroad should not be considered definitively diagnosed on that basis alone, and should still be worked up with culture where possible.^[1]

When to test

Any fever in a traveller returned from a typhoid-endemic region — especially South Asia — warrants active testing rather than reassurance based on a benign-appearing early presentation, mirroring the same testing discipline used for a febrile returned traveller from a malaria-endemic area.

• Prevent infection in the first place through destination-appropriate pretravel vaccination plus food and water safety counselling — never one without the other, since neither vaccine is close to fully protective.
• Confirm the diagnosis promptly (ideally before starting antibiotics, since prior antibiotic exposure reduces blood-culture sensitivity) and initiate appropriate empiric therapy without unnecessary delay.
• Select empiric antibiotic therapy that reflects current regional resistance patterns rather than older fluoroquinolone-first teaching, particularly for infection acquired in or of uncertain origin from South Asia.
• Recognize and urgently manage the serious complications of untreated or delayed-treated disease — intestinal perforation and gastrointestinal hemorrhage foremost among them.
• Identify and appropriately manage the chronic carrier state, including the food-handler/occupational and public-health reporting obligations it carries.
• Counsel every traveller — vaccinated or not — that food and water safety precautions remain necessary for the full duration of travel to an endemic area.

Step 2 — choose between the 2 licensed vaccines

Both vaccines provide comparable, moderate protection (roughly 50% efficacy against clinical disease over about 2-3 years of follow-up in trial data) — genuinely useful, but nowhere close to complete, which is the basis for the food/water counselling message that must accompany either choice.^[2]

Step 4 — counsel every vaccinated traveller on the same point, without exception

Neither vaccine is close to fully protective (roughly 50% efficacy), and neither reliably protects against paratyphoid fever at all.^[2][3] Food and water safety precautions — safe water sources, cooked/peeled food, avoiding ice of uncertain origin — remain necessary for the entire trip regardless of vaccination status; vaccination reduces risk, it does not replace behavioural precautions.

Uncomplicated disease, tolerating oral intake

Severe or complicated disease

Hospitalize and start parenteral therapy immediately: ceftriaxone 2 g IV once daily (adult), or 50-100 mg/kg (maximum 4 g) IV once daily (pediatric), then transition to oral azithromycin to complete at least 7 days total once the patient is stable and tolerating oral intake.^[6] For a patient with altered consciousness or shock, dexamethasone (1 mg/kg IV loading dose, then 0.25 mg/kg IV every 6 hours for 48 hours) is an established adjunct that has been shown to reduce mortality in this specific subgroup.^[6] For suspected intestinal perforation or peritonitis, add metronidazole to ceftriaxone for anaerobic coverage and obtain an urgent surgical consultation — surgical exploration with simple closure is usually curative when performed promptly.^[6]

• Food and water safety counselling is not optional context — it is the primary defence against both typhoid and paratyphoid, since neither is fully prevented by vaccination: safe (bottled, boiled, or properly treated) water, food that is cooked and served hot, fruit the traveller peels themselves, and avoiding ice of uncertain origin.
• Meticulous hand hygiene, particularly before eating and after using the toilet — both for the traveller's own protection and, for anyone recovering from infection, to reduce onward transmission risk to others.
• During acute illness: supportive care with adequate oral or IV hydration, and an antipyretic such as acetaminophen for symptomatic fever control.
• Exclude a person with acute typhoid or paratyphoid infection from food handling and, where relevant, direct patient care duties until public health clearance criteria are met.
• Typhoid fever is a nationally notifiable disease in Canada — report every confirmed case to the relevant provincial or territorial public health authority, which leads contact tracing and any food-handler investigation.^[4]

Pregnancy

Ty21a is contraindicated in pregnancy.^[7] Vi polysaccharide has no dedicated pregnancy safety data but may reasonably be considered when travel to a high-risk destination cannot be deferred and exposure is genuinely likely, following an explicit discussion of benefits and unknowns — deferring travel to South Asia altogether is preferable when feasible.^[1] For treatment of confirmed infection in pregnancy, azithromycin and ceftriaxone are both considered safe; avoid fluoroquinolones as a matter of standard obstetric caution, using azithromycin or a cephalosporin instead.^[6]

Pediatrics

Ty21a is approved from age 6 years; Vi polysaccharide is approved from age 2 years — for a younger child, Vi polysaccharide is the only licensed option.^[7][9] Dose all treatment antibiotics by current body weight (see Drug Tables). Fluoroquinolone use in children has traditionally been limited by a theoretical arthropathy concern from animal data; in practice, this is weighed against the risk of a life-threatening, difficult-to-treat infection, and a fluoroquinolone may still be reasonable in a child with a confirmed-susceptible or highly resistant infection where better options are unavailable — this is a specialist-level judgment call, not a default choice.

Immunocompromise, including HIV

Ty21a is contraindicated in any immunocompromised traveller, including HIV infection, since it is a live attenuated vaccine.^[7] Vi polysaccharide is not a live vaccine and is the appropriate alternative for this population, with the same caveat that it remains only moderately effective.^[1]

Breastfeeding

Both licensed vaccines and the standard treatment antibiotics discussed in this chapter (azithromycin, ceftriaxone) are generally considered compatible with breastfeeding; individualize any specific concern with the treating clinician.

Food handlers and healthcare workers

This population needs explicit counselling that a confirmed infection carries occupational, not just personal, implications — exclusion from food handling or direct patient care is required until clearance testing criteria are met, and any identified chronic carrier in this occupational group needs coordinated public health and workplace follow-up, as illustrated directly by the Ottawa, Canada outbreak.^[4]

Fever can reasonably take 3-5 days to resolve even on fully appropriate antibiotic therapy — this is an expected part of the clinical course, not evidence of treatment failure, and should be explained to the patient in advance to avoid unnecessary alarm or premature antibiotic switching.^[1][6] If fever has not meaningfully improved by day 5 of appropriate therapy, reassess for a resistant organism (repeat cultures with susceptibility testing), an undrained focus of infection (abscess), or an alternative diagnosis, rather than simply extending the same regimen.^[1]

Relapse: genuine relapse can occur in up to about 10% of patients, typically 2-3 weeks after apparent recovery, and is not usually related to antimicrobial resistance in the original strain — counsel every patient to seek care promptly if fever recurs after a period of feeling well, and retreat with an appropriate course when this occurs.^[1][6]

Report every confirmed case — acute infection or identified chronic carrier — to the relevant provincial or territorial public health authority; typhoid is a nationally notifiable disease in Canada, and carrier identification specifically triggers occupational food-handling exclusion until clearance is documented.^[4]

1. Fever persisting beyond 5 full days of appropriate antibiotic therapy: reassess rather than assume failure prematurely, but do investigate — repeat blood cultures with susceptibility testing, evaluate for an undrained abscess or other persistent focus, and reconsider the diagnosis.^[1]
2. Clinical deterioration, new peritoneal signs, or evidence of gastrointestinal bleeding at any point: treat as a surgical/medical emergency — urgent surgical consultation, broaden antibiotic coverage to include anaerobic cover (add metronidazole to ceftriaxone, or use meropenem alone), and involve infectious disease.^[6]
3. Relapse 2-3 weeks after apparent recovery: retreat with an appropriate antibiotic course; this is not usually a resistance problem and does not necessarily require switching drug class.^[1]
4. No improvement on ceftriaxone as expected, or any travel history to Pakistan specifically: escalate empiric coverage to meropenem plus azithromycin and obtain infectious disease consultation, given the documented XDR and ceftriaxone-resistant strains circulating in that region.^[10][6]
5. Confirmed chronic carrier (positive culture 12 months or more after acute infection): prolonged high-dose antibiotic therapy (commonly a fluoroquinolone-class agent for 4-6 weeks where susceptibility allows) achieves an 80-90% cure rate in a carrier with a normal biliary tract, but is substantially less effective when gallstones and biofilm are present; cholecystectomy improves — but does not guarantee — eradication in that setting, and mandatory public health reporting and food-handling exclusion apply regardless of which approach is chosen.^[4]
6. Any diagnostic uncertainty, XDR-region travel history, or difficulty achieving source control in complicated disease: involve infectious disease or tropical medicine expertise directly rather than troubleshooting empirically.

• Treating typhoid vaccination as complete protection and relaxing food/water safety counselling — neither licensed vaccine is close to fully protective, and neither reliably covers paratyphoid fever at all.^[2][3]
• Defaulting to empiric fluoroquinolone therapy for infection acquired in, or of uncertain origin from, South Asia — this is outdated teaching given well over 99% documented decreased ciprofloxacin susceptibility in that region.^[1][3]
• Excluding typhoid from the differential because relative bradycardia or rose spots are absent — both signs are genuinely insensitive (relative bradycardia sensitivity is only about 15-20%) even though they are useful when present.^[5]
• Treating a single negative blood culture as definitively ruling out typhoid, especially in a patient who received antibiotics before the sample was drawn — sensitivity is only about 50% for a single culture.^[1]
• Co-administering Ty21a with an antibiotic, or failing to separate it appropriately from atovaquone-proguanil (at least 10 days) — this can inactivate the live vaccine strain and leave the traveller unprotected without either party realizing it.^[1]
• Giving Ty21a to a pregnant or immunocompromised traveller — use Vi polysaccharide instead.^[7]
• Declaring antibiotic treatment a failure before day 5, when 3-5 days of ongoing fever on appropriate therapy can be an expected part of the clinical course.^[1]
• Missing chronic-carrier screening and follow-up in a food handler or healthcare worker after a confirmed infection — this is exactly the gap that allowed the Ottawa, Canada outbreak to continue undetected for nearly 4 years.^[4]
• Assuming a returned traveller's paratyphoid risk was covered by their typhoid vaccination — it generally was not.^[2]
• Missing an acute abdomen or GI bleeding as a typhoid complication in a patient roughly 2-3 weeks into untreated or inadequately treated illness — this is exactly the window when intestinal perforation and hemorrhage most often occur.^[6]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Typhoid Vaccines

Neither vaccine is in this platform's drug database (vaccines are outside its scope) — both are rendered here as plain text. Both are roughly 50% effective and neither reliably covers paratyphoid fever.

First-Line Treatment — Macrolide and Cephalosporins

Preferred for South-Asia-acquired or resistance-unknown infection given high regional fluoroquinolone resistance.

Fluoroquinolones — Confirmed-Susceptible Infection Only

No longer appropriate as a blind empiric default, particularly for South-Asia-acquired infection, given well over 99% documented decreased ciprofloxacin susceptibility in that region.

Severe/Complicated Disease — Carbapenem and Adjuncts

For extensively drug-resistant (XDR) or ceftriaxone-resistant infection, and for the shock/altered-consciousness or perforation subgroups of severe disease.