Enteric fever

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

S. Typhi and S. Paratyphi are human-restricted pathogens. After surviving gastric acid they invade ileal lymphoid tissue, multiply within macrophages and disseminate through the reticuloendothelial system. A secondary bacteraemia produces sustained fever and multisystem illness. Necrosis of Peyer patches can cause lower gastrointestinal bleeding or perforation, commonly in the second or third week if effective treatment is delayed.

Risk assessment should record exact countries and dates, visiting-friends-and-relatives travel, food and water exposures, typhoid vaccination, previous antibiotics, hospital attendance overseas and household illness. Vaccination reduces but does not eliminate typhoid risk and does not provide dependable protection against paratyphoid. Previous antimicrobial exposure can suppress cultures without excluding infection.

Antimicrobial resistance is central rather than incidental. Fluoroquinolone non-susceptibility is widespread, extended-spectrum beta-lactamase-producing and extensively drug-resistant Typhi occur, and susceptibility may change the definitive agent. Empirical selection therefore depends on severity, place of acquisition, recent antibiotics and local or national surveillance, with microbiology or infection ownership.

Key points

Enteric fever is systemic infection caused by Salmonella enterica serovars Typhi or Paratyphi, usually acquired through food or water contaminated by human faeces.
Think of sustained fever with headache, malaise and abdominal symptoms after travel to South Asia or another endemic region; diarrhoea, constipation or no bowel disturbance are all possible.
Blood culture is the first-line diagnostic test and should be obtained before antimicrobials whenever this does not delay treatment of a severely unwell patient.
Send stool culture as an additional investigation, but a negative stool result does not exclude acute disease; bone-marrow culture is more sensitive but is reserved for specialist diagnostic difficulty.
For uncomplicated disease without an extensively drug-resistant exposure, oral azithromycin 500 mg once daily for seven days is a current UK specialist-supported empirical option.
Complicated infection ordinarily requires intravenous ceftriaxone 2 g once daily; suspected complicated extensively drug-resistant disease may require meropenem plus azithromycin pending susceptibility.
Do not choose ciprofloxacin empirically because fluoroquinolone non-susceptibility is common; use it only when the isolate is fully susceptible and the specialist plan supports it.
Typhoid and paratyphoid are notifiable diseases in England. Notify on clinical suspicion and cooperate with the health protection team on exclusion, contact assessment and clearance cultures.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Human-restricted Salmonella

S. enterica serovars Typhi and Paratyphi circulate only through infected people or carriers, reaching new hosts by faecally contaminated food or water.

Travel exposure

Most UK cases follow travel to endemic regions, especially South Asia, with greater risk during visits to friends and relatives and prolonged local food exposure.

Chronic carriage

A minority continue shedding after illness, often from gallbladder colonisation associated with gallstones, creating an asymptomatic reservoir for later transmission.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Mucosal invasion
Organisms survive gastric acid, cross ileal M cells and enter Peyer patches, where uptake by macrophages permits intracellular persistence.
2
Reticuloendothelial spread
Infected macrophages transport bacteria to mesenteric nodes, liver, spleen and marrow before secondary bacteraemia produces sustained systemic inflammation.
3
Ileal ulceration
Hyperplasia and necrosis of Peyer patches create longitudinal terminal-ileal ulcers that may erode vessels or perforate the bowel wall.
4
Biliary persistence
Survival in bile and gallbladder biofilm allows intermittent faecal shedding after symptoms resolve and explains some chronic carrier states.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Progressive febrile illnessRed flag

Fever usually rises over several days with headache, marked malaise, anorexia, dry cough or myalgia; the patient may look disproportionately unwell despite few focal signs.

Abdominal phenotype

Diffuse discomfort, right iliac fossa pain, diarrhoea, constipation, nausea, vomiting or abdominal distension can occur, and bowel habit alone cannot distinguish typhoid from paratyphoid.

Examination clues

Hepatosplenomegaly, coated tongue, faint truncal rose spots and pulse-temperature dissociation are recognised clues but are insensitive; their absence should never reassure.

Neurological diseaseRed flag

Confusion, delirium, reduced consciousness, seizure or focal neurology may accompany severe disease and should prompt glucose measurement, sepsis care and assessment for meningitis or cerebral malaria.

Intestinal complicationRed flag

New bleeding, abrupt severe pain, involuntary guarding or septic deterioration after a longer febrile course suggests ileal ulcer haemorrhage or perforation.

Red flags requiring action

Hypotension, altered consciousness, rising lactate, oliguria or respiratory compromise indicates severe infection and requires immediate sepsis care.
Sudden worsening abdominal pain, guarding, rigidity, free air or unexplained deterioration suggests terminal ileal perforation and needs urgent surgical assessment.
Melaena, haematochezia, haematemesis, falling haemoglobin or circulatory instability can represent enteric-fever intestinal haemorrhage.
Travel from Pakistan, Iraq or another setting with extensively drug-resistant strains changes empirical therapy and demands immediate specialist microbiology advice.
Fever after tropical travel still requires urgent malaria films; identifying enteric fever does not safely exclude malaria or another concurrent infection.
Pregnancy, infancy, advanced age, immunosuppression and inability to take oral treatment lower the threshold for admission and intravenous therapy.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line blood culturesFirst stepFirst line
Why
Confirm bacteraemia, identify Typhi or Paratyphi and generate the susceptibility profile that controls definitive therapy.
Interpretation and limitations
Take at least two appropriately filled sets before antimicrobials when safe and state travel details. Sensitivity falls after antibiotics; a negative result does not end investigation when the syndrome fits.
02
Stool culture
Why
Provide additional organism recovery during acute illness and support later public-health clearance where directed.
Interpretation and limitations
Yield varies with illness stage and intermittent shedding. A positive result supports diagnosis, but acute blood culture remains more useful and clearance sampling must follow the health protection schedule.
03
Susceptibility and reference testing
Why
Determine fluoroquinolone, azithromycin, ceftriaxone and carbapenem activity and identify resistant phenotypes.
Interpretation and limitations
Act on the reported MIC or category rather than assumed geographic susceptibility. Discuss resistant, discordant or clinically failing isolates with microbiology and the relevant reference laboratory.
04
Severity and complication panel
Why
Detect cytopenias, hepatitis, renal injury, coagulopathy, dehydration and occult bleeding.
Interpretation and limitations
Request FBC, renal profile, liver tests, CRP, glucose, lactate, coagulation and group-and-save; trend haemoglobin and lactate when bleeding or shock is possible.
05
Targeted imaging
Why
Identify perforation, abscess, cholecystitis or another source when focal signs or deterioration occur.
Interpretation and limitations
Urgent contrast CT abdomen is generally most informative in a stable adult with peritonism or unexplained deterioration; do not delay surgical review for imaging in an unstable abdomen.
06
Concurrent imported-fever testing
Why
Avoid missing a more immediately lethal or coexisting travel-associated infection.
Interpretation and limitations
Obtain urgent malaria films and rapid testing when exposure fits, then add dengue, hepatitis, leptospira, rickettsial or viral-haemorrhagic-fever assessment according to itinerary and risk.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Malaria

Fever, headache, cytopenias and gastrointestinal symptoms overlap; urgent serial parasite testing remains mandatory whenever geographic exposure is plausible.

Dengue

Fever, headache, thrombocytopenia and abdominal warning symptoms may mimic enteric fever, but exposure, rash, capillary leak and virology help distinguish it.

Leptospirosis

Freshwater or animal-urine exposure, conjunctival suffusion, myalgia, jaundice and renal injury suggest leptospirosis, confirmed with appropriately timed molecular or serological testing.

Rickettsial infection

An eschar, rash or arthropod exposure supports rickettsiosis, but these clues may be absent and specialist empirical treatment may be time critical.

Non-travel sepsis

Pyelonephritis, pneumonia, intra-abdominal infection, endocarditis and viral illness can produce sustained fever and must be investigated in parallel.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SAMPLE FIRSTInvestigate suspected enteric feverFirst stepSustained fever or compatible systemic illness follows residence in or travel to an endemic setting.

1Perform ABCDE, establish dates and exact locations, review antibiotics and vaccination, and assess for bleeding, peritonism, encephalopathy and shock.
2Take blood-culture sets before antimicrobials if this can be done immediately; add stool culture, severity bloods and urgent malaria testing without allowing sampling to delay resuscitation.
3Notify suspected typhoid or paratyphoid according to national arrangements and contact the health protection team early for risk-group, household and occupational advice.
4Ask microbiology or infection specialists to select empirical treatment from severity, likely geography and current resistance data, then narrow when organism and susceptibility are known.

02UNCOMPLICATEDTreat stable oral diseaseThe patient has no shock, organ dysfunction, gastrointestinal complication or absorption problem and reliable follow-up is possible.

1For disease without an extensively drug-resistant exposure, use oral azithromycin 500 mg once daily for seven days as a supported empirical regimen, checking interactions and pregnancy.
2Review within 48 to 72 hours because fever may resolve slowly; confirm adherence, culture result and susceptibility rather than changing treatment for fever alone in a stable improving patient.
3If a culture-confirmed isolate is fully ciprofloxacin susceptible, a specialist may use ciprofloxacin 500 mg orally twice daily to complete seven days; do not infer susceptibility from a nalidixic-acid or geography shortcut.
4EscalationEscalate to admission and intravenous treatment for vomiting, clinical deterioration, new focal abdominal signs or inability to guarantee completion and public-health follow-up.

03COMPLICATEDStabilise severe or complicated diseaseSepsis, organ dysfunction, encephalopathy, uncontrolled vomiting, bleeding, perforation or another focal complication is present.

1Resuscitate carefully, obtain cultures immediately, involve infection, microbiology and critical care, and use intravenous ceftriaxone 2 g once daily when the likely isolate is not extensively drug resistant.
2For severe disease acquired where extensively drug-resistant Typhi is plausible, discuss meropenem 1 g intravenously every eight hours plus azithromycin 500 mg daily pending susceptibility, adjusting meropenem for renal function.
3Seek urgent surgical input for peritonism, free gas, uncontrolled haemorrhage or abscess; antibiotics cannot replace source control for perforated ileum.
4Individualise duration to organism, complications, source control and response; resistant complicated disease commonly needs at least ten days of active parenteral treatment and therapy until sustained clinical improvement.

04NARROWConvert to definitive therapyDefinitiveSpecies identification and reliable antimicrobial susceptibility results become available.

1Confirm the specimen, serovar, MIC interpretation and any reference result with microbiology, then stop unnecessary combination or overly broad treatment.
2Use oral step-down only after haemodynamic stability, improving abdominal findings, reliable absorption and an active oral option have been established.
3Investigate persistent fever with repeat cultures, adherence review and imaging for a complication; recognise that defervescence can take several days despite effective therapy.
4Document the complete course, susceptibility profile, notification and post-treatment sampling plan before discharge or transfer.

05PUBLIC HEALTHControl onward transmissionTyphoid or paratyphoid is suspected or confirmed in a person living, working or studying in the UK.

1Follow health protection instructions on exclusion: symptomatic people remain away from work or school until at least 48 hours after their last symptom, with stricter rules for designated risk groups.
2Risk-group clearance ordinarily requires three negative faecal samples, beginning at least one week after antimicrobial completion and collected at least 48 hours apart.
3Do not improvise screening or antibiotic treatment for household contacts; provide names and exposure information so the health protection team can risk-assess contacts.
4Reinforce meticulous hand hygiene, safe toilet cleaning, food handling restrictions and avoidance of food preparation for others while exclusion applies.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

First-line oral empirical option for uncomplicated infection in current British Infection Association guidance.

Azithromycin

Give 500 mg orally once daily for seven days for uncomplicated susceptible or presumed non-extensively-drug-resistant enteric fever, unless specialist advice selects a different course.

Review QT prolongation, interacting medicines, liver disease and pregnancy; vomiting or severe disease makes oral monotherapy unreliable, and susceptibility or clinical failure must prompt specialist reassessment.

First-line parenteral option for complicated non-XDR enteric fever while cultures and susceptibility are pending.

Ceftriaxone

Give 2 g intravenously once daily for complicated infection without a strong extensively-drug-resistant exposure, then step down only to a confirmed active oral agent when clinically appropriate.

Check immediate beta-lactam allergy, biliary disease and local resistance; extended-spectrum beta-lactamase-producing Typhi may be resistant, so review every isolate result promptly.

Specialist empirical combination where geography and severity create a credible XDR or extended-spectrum beta-lactamase risk.

Meropenem plus azithromycin

For suspected severe extensively drug-resistant disease, use meropenem 1 g intravenously every eight hours plus azithromycin 500 mg orally or intravenously once daily pending expert susceptibility review.

Adjust meropenem for renal impairment, review seizure risk and de-escalate rapidly; a carbapenem is not routine treatment for uncomplicated travel-associated fever.

Narrow definitive option only for laboratory-confirmed susceptible isolates, not a default empirical drug.

Ciprofloxacin

When the recovered isolate is confirmed fully susceptible, a specialist-supported regimen is 500 mg orally twice daily to complete seven days for uncomplicated disease.

Apply current fluoroquinolone safety restrictions, including tendon, neurological, psychiatric, aortic and dysglycaemic risks; consider pregnancy, interactions and renal adjustment.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Intestinal haemorrhage

Peyer-patch ulceration can erode mesenteric vessels, causing occult blood loss, melaena, major lower gastrointestinal bleeding and haemodynamic collapse.

Ileal perforation

Transmural ulceration causes peritonitis, polymicrobial secondary sepsis and shock, requiring urgent surgery alongside broad antimicrobial treatment.

Neurological dysfunction

Severe systemic infection may cause delirium, encephalopathy, seizures or reduced consciousness and is associated with a worse prognosis.

Focal seeding

Bacteraemia can seed bone, joints, endovascular structures, gallbladder or other sites, particularly with haemoglobinopathy, prosthetic material or immunosuppression.

Relapse and carriage

Incomplete clearance may produce recurrent fever after apparent recovery or prolonged asymptomatic shedding with ongoing public-health implications.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Record temperature, haemodynamics, mental state, abdominal findings, oral intake, urine output and stool frequency daily; deterioration matters more than delayed defervescence alone.
Trend FBC, renal and liver profiles and CRP; repeat haemoglobin and coagulation urgently when gastrointestinal bleeding is suspected.
Review culture identification and susceptibility every day, confirm an active regimen and document why broad or combination therapy remains necessary.
Repeat blood cultures for persistent sepsis, recurrent fever after initial improvement or suspected endovascular infection rather than as a routine ritual in every improving case.
Arrange clear review for relapse during the weeks after treatment and ensure the health protection team controls any faecal clearance schedule.
Before discharge, reconcile occupational or school exclusion, contact advice, hand hygiene, treatment completion and the named team responsible for outstanding results.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Fever can resolve slowly

A stable patient may remain febrile for several days after active therapy begins; worsening physiology, persistent bacteraemia or a focal complication is more concerning than temperature alone.

Stool culture has two roles

During illness it can support diagnosis, while after treatment specifically timed specimens assess clearance in selected risk groups; the purposes and timing should not be confused.

Vaccination is incomplete protection

Available vaccines reduce typhoid risk but do not eliminate it and provide no reliable paratyphoid protection, so compatible post-travel fever still needs cultures.

Carriage is a public-health problem

Persistent biliary or intestinal shedding may be asymptomatic, particularly with gallbladder disease; eradication and any further investigation require specialist and health-protection coordination.

Resistance follows geography

The country and sometimes region of acquisition can change empirical therapy, but only isolate susceptibility can safely determine definitive narrowing.

11Common pitfallsFrequent interpretation and management errors.

01
Do not dismiss enteric fever because the patient has constipation rather than diarrhoea, lacks rose spots or does not show relative bradycardia.
02
Do not wait for stool culture when blood cultures can be obtained promptly, and do not use Widal serology to establish acute infection.
03
Do not start empirical ciprofloxacin simply because it was historically standard; contemporary resistance makes susceptibility essential.
04
Do not allow cultures to postpone antimicrobials in shock, perforation or another time-critical severe presentation.
05
Do not assume antimicrobial completion automatically ends exclusion from food handling, healthcare, nursery work or attendance; health protection decides clearance requirements.
06
Do not overlook malaria, viral haemorrhagic fever risk assessment or another concurrent imported infection because one test has returned positive.