Typhoid and enteric fever

• Enteric fever is a systemic bacterial infection caused by Salmonella enterica serovar Typhi (typhoid fever) or serovar Paratyphi A, B or C (paratyphoid fever), and only humans carry these organisms.
• It begins gradually with a rising fever over several days, spreads via the bloodstream, and can look like many other febrile illnesses; blood culture, or sometimes bone marrow culture, is how the diagnosis is confirmed.
• Without effective antibiotics, enteric fever lasts weeks, can bleed or perforate the intestine, and historically killed 10 to 30% of patients; with prompt appropriate treatment, death is now under 1%.
• Treatment must be guided by antimicrobial susceptibility and travel history: azithromycin or a carbapenem are often safer starting choices than fluoroquinolones, because most isolates from South Asia are resistant.
• Prevention rests on safe water, food and hand hygiene plus vaccination, but vaccines are only 50 to 80% protective, so they never replace hygiene.

By the end of this page you should be able to:

1. Classify typhoid and paratyphoid fever and explain how S. Typhi and S. Paratyphi differ.
2. Describe the step-by-step path from swallowing the organism to fever, bowel ulceration, and bacteraemia.
3. Recognise the clinical picture across the weeks of illness, including complications and how it mimics malaria and other infections.
4. Choose investigations rationally, explaining why blood, bone marrow, and stool cultures differ in yield, and why serology is not reliable.
5. Plan empiric and directed treatment from resistance patterns and travel history, with doses, routes, and durations, and know when surgery is needed.
6. Explain chronic carriage, how it is treated, and which patients need cholecystectomy.
7. Compare the typhoid vaccines, their ages, schedules, and limits, and counsel a traveller accurately.

Paratyphoid fever is clinically almost indistinguishable from typhoid fever, although some sources describe paratyphoid as somewhat less severe and with a roughly half-sized case fatality compared with typhoid fever.^[2] Other sources argue that S. Paratyphi A can cause disease as severe as S. Typhi.^[4]

The illness is not a simple diarrhoea. Many patients never have diarrhoea at all, and the central problem is invasion of the lymphoid tissue of the small bowel followed by prolonged bacteraemia. Because the two serovars share the same transmission route, preventive measures are the same for both; the main difference is that paratyphoid A has become a steadily larger share of enteric fever in parts of Asia.^[4]

Global estimates differ by method and year, but the burden is large wherever safe water and sanitation are limited. A 2026 CDC travel medicine chapter estimates about 9.2 million cases of typhoid fever and 3.8 million cases of paratyphoid fever worldwide each year, causing about 133,000 deaths, with Africa and south Asia carrying the greatest share.^[2] Older reviews give higher figures of 13 to 17 million typhoid cases and 600,000 deaths a year, concentrated in Asia, and note that many mild cases never reach formal diagnosis.^[5]

• Who gets infected. Disease occurs in school-aged children and young adults in endemic areas, with both sexes affected equally, although much illness is treated at home or in clinics and never appears in hospital data.^[4]
• Travel-related disease. In the United States, before the COVID-19 pandemic, roughly 450 culture-confirmed typhoid and 130 paratyphoid A cases were reported annually, falling to roughly 150 to 160 typhoid and 30 to 50 paratyphoid A cases during 2020 to 2021. About 85% of typhoid and 80% of paratyphoid cases in the United States are in international travellers, and more than 70% of these travellers return from South Asia, mainly Bangladesh, India and Pakistan. Travellers visiting friends and relatives are at particular risk, and infection can be acquired during visits of less than one week to highly endemic areas. Paratyphoid caused by S. Paratyphi B or C is rarely reported.^[2]
• Age. Severe and fatal disease is associated with extremes of age, and children in south Asia carry a high burden.^[4]

Humans are the only source of these organisms, and no animal or environmental reservoir has been identified. Transmission is by the faecal-oral route: water or food contaminated by faeces or urine from an acutely ill person, a convalescent person, or a chronic carrier.^[2]

Risk factors that matter in practice include:

• Travel and mass gatherings in areas where the disease is endemic, especially south Asia.^[2]
• Food and water exposure. Contaminated water, undercooked food, ice and ice cream, and food prepared by persons with recent endemic exposure. The organism is acid-sensitive, so a reduced gastric acid barrier favours infection, and food handlers who are carriers are an important source. Helicobacter pylori antibody positivity has been associated with typhoid fever in case-control studies (adjusted odds ratio around 2.0), although this may reflect shared poor hygiene rather than a true causal link through reduced stomach acid.^[4]
• Host factors. Past gastric surgery, antacid use, proton pump inhibitors and conditions reducing acid secretion increase susceptibility. ^[4]
• Sickle cell disease and other vulnerabilities of the reticuloendothelial system are a useful background when deciding how aggressively to investigate a febrile traveller. ^[4]
• Intimate exposure to a documented chronic carrier is a defined indication for immunisation.^[3]

The reasoning behind almost every symptom follows from four facts: the organism is only slightly acid-resistant, it must reach the lower small bowel, it grows inside macrophages, and it can later hide in the gallbladder.

1. Surviving the stomach. S. Typhi and Paratyphi are sensitive to acid, and anything that lowers the gastric barrier (medication, surgery, infection) increases the chance of illness. ^[4]
2. Invasion of the ileum. The organisms reach the terminal ileum and colonise the lymphoid patches (Peyer patches), then invade through M cells into mucosa and are taken up by macrophages. ^[4]
3. Bacteraemia and the incubation period. After an incubation that is typically 6 to 30 days, and can range from 3 to 60 days, the organism reaches the bloodstream. Higher infective doses raise attack rates and shorten the interval to bacteraemia, but do not change the time to symptoms or severity. Human challenge studies show that some people develop a silent bacteraemia and shed the organism in stool before they ever feel ill. ^[4]
4. Fever and systemic illness. Fever often rises in steps over the first few days and reaches a plateau of 39 to 40 degrees Celsius that can persist for days or weeks, with little daily variation unless antipyretics are given. Bacteraemia and endotoxin release drive the systemic picture: headache, malaise, abdominal pain, a dry cough, and a characteristic apathetic rather than toxic appearance. ^{[4] [5]}
5. Third-week complications. In untreated or inadequately treated illness, ulceration of the Peyer patches can erode an enteric vessel (gastrointestinal bleeding) or perforate the ileum. These complications cluster in the second to fourth week. ^[4]
6. Gallbladder carriage. The organism can persist in the gallbladder and biliary tree, leading to intermittent faecal shedding and, in a small minority, chronic carriage; chronic carriers have an increased risk of gallbladder carcinoma. ^[4]

Relative bradycardia is often quoted as typical, but some evidence suggests tachycardia is commoner and that bradycardia is neither sensitive nor specific for enteric fever. ^[4] Rigors are uncommon and this can help distinguish enteric fever from malaria. ^[4]

Rose spots, a transient blanching maculopapular rash of 2 to 4 millimetre lesions on the trunk, occur in 1 to 30% of cases and are easy to miss in dark-skinned patients. ^[4]

The characteristic lesion is hyperplasia and ulceration of ileal Peyer patches, which in the third week can bleed or perforate. Hepatosplenomegaly reflects reticuloendothelial hyperplasia. Most of these descriptions are gross pathological findings; they are included here to explain why bleeding and perforation are ileal rather than gastric, and why surgical resection of the affected segment is preferred when perforation occurs.

• First week. Insidious onset with a gradually rising fever, frontal headache, malaise, anorexia, and abdominal pain. Constipation is more common early, though many have diarrhoea at some point, and vomiting is more common in children. Dry cough, sore throat, myalgia and, rarely, epistaxis can occur. ^[4][2]
• Second week. High plateau fever of 39 to 40 degrees Celsius with a dulling headache and an apathetic, flushed appearance. Hepatosplenomegaly becomes detectable. Relative abdominal tenderness, often a soft, slightly distended "doughy" abdomen, is typical. ^[4]
• Third to fourth week (untreated). Weight loss, weakness, altered mental state, delirium, typhoid facies, tremor and ataxia, and the ten-to-fifteen-percent complication rate. ^[4][2]
• Children. Diarrhoea and vomiting are more frequent, and febrile convulsions, nephritis, jaundice and typhoid meningitis occur more often than in adults. ^[4]
• Pregnancy. Typhoid fever can complicate pregnancy and may cause miscarriage or rare neonatal infection, although treatment appears to reduce these risks. ^[4]

• fever with relative bradycardia that is, at most, a soft sign;
• diffuse abdominal tenderness with a soft, distended abdomen;
• hepatosplenomegaly in most patients;
• rose spots on the trunk, seen in 1 to 30% of cases and easily missed;
• scattered wheeze, which can suggest pneumonia;
• in severe disease, apathy, tremor, ataxia, or reduced responsiveness. ^[4]

A low-grade fever that rises daily, combined with a travel or exposure history, should make you suspect enteric fever even before culture results.

Fever in a returned traveller is broader than enteric fever, and the differential should include malaria (rigors are more typical), dengue, rickettsial disease, viral haemorrhagic fevers, viral hepatitis, amebiasis, tuberculosis, bacteraemia from other sources, and pneumonia. ^[2][4]

Enteric fever is a nationally notifiable disease in some health systems precisely because it is so easily missed among other febrile illnesses.

The principle is to confirm the organism and, at the same time, obtain enough susceptibility information to choose an effective antibiotic. No bedside test has adequate sensitivity and specificity, so the initial diagnosis is often clinical while cultures are awaited. ^[2][3]

• Blood culture is the mainstay. A single sample is positive in roughly 50% of cases, so multiple sets taken over the first few days improve yield, and cultures may need to be held for up to 7 days. Sensitivity estimates range from 50 to 70% depending on the source. ^[2][5]
• Bone marrow culture is more invasive but is the most sensitive standard method, with yields reported around 80 to 90%, and it is relatively unaffected by up to five days of prior antibiotics, which makes it valuable for partially treated patients. ^[2][5]
• Stool and urine culture are less frequently positive during the first week, and stool culture is more often positive in children than adults. ^[2][5]
• Duodenal (string) culture, rose-spot biopsy, and urine culture can add yield in difficult cases. ^[3][5]
• Multiplex PCR panels detect nucleic acid rather than viable organisms, so results must be interpreted in context, and a positive panel should still be followed by culture for susceptibility and public-health typing. ^[3]
• Serological tests such as the Widal test are not recommended for diagnosing acute infection. They cannot distinguish acute infection from past infection or vaccination, and they produce a high rate of false positives. ^[1][2][3]

• Blood cultures should be taken from anyone with suspected sepsis or enteric fever, infants under 3 months, people with systemic illness, immunocompromise or high-risk conditions, and travellers from endemic areas with unexplained fever. ^[3]
• Imaging is reasonable when there is sustained fever despite adequate antibiotics, or to assess possible intestinal perforation or deep-seated infection (chest radiograph for free air, ultrasound for collections). ^[3]
• Positive cultures should be reported to public-health authorities, because enteric fever is notifiable in many jurisdictions and domestic cases trigger an investigation into the source. ^[2][3]

There are no formal clinical diagnostic criteria beyond culture confirmation. Where culture capacity is limited, a diagnosis is supported by a compatible travel or exposure history, a gradual fever rising over days, hepatosplenomegaly, and the absence of a more obvious focus. ^[2][3]

More than 90% of patients can be managed outside hospital with oral antibiotics, a reliable carer and close follow-up. Supportive care is nonetheless the foundation: rehydration by mouth or intravenously, tepid sponging, nutrition, and correction of anaemia. ^[5]

• Check and treat dehydration exactly as you would for other febrile illnesses; severe dehydration, shock or ileus requires intravenous isotonic fluid.
• Nutrition should continue; do not restrict feeding.
• Avoid salicylates and antipyretics that provoke heavy sweating and hypotension, and avoid precipitate cooling. ^[5]
• Dexamethasone has a defined role in severe disease: 3 mg/kg intravenously followed by eight doses of 1 mg/kg every 6 hours, for patients with altered mental status or shock; prolonged steroid use beyond 48 hours may increase the relapse rate. ^[5]

Treatment decisions need a travel history, because resistance patterns vary by region. IDSA guidance is that people with suspected sepsis and suspected enteric fever should be treated empirically with broad-spectrum antibiotics after cultures are collected, and therapy should then be narrowed once susceptibility results are available. ^[3]

The CDC algorithms summarise the travel-based approach:

• For patients who travelled to Iraq or Pakistan, or who did not travel internationally, uncomplicated illness may be treated empirically with azithromycin, and complicated illness with a carbapenem. ^[1][2]
• For travellers returning from most other countries, ceftriaxone and azithromycin remain appropriate empiric options. ^[1][2]
• Most infections diagnosed in the United States are not susceptible to fluoroquinolones, so fluoroquinolones should not be used for empiric treatment there. ^[1][2]
• Susceptible isolates in adults can still be treated with a fluoroquinolone, and fluoroquinolones penetrate macrophages and bile well, so resistance patterns rather than habit should drive the choice. ^{[5] [2]}

If susceptibility results are unavailable and the diagnosis is still likely, choose empiric treatment based on the susceptibility pattern of the probable country of acquisition. ^[1][3]

XDR typhoid, first described in the Sindh outbreak in Pakistan in 2016, is resistant to ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin and trimethoprim-sulfamethoxazole but usually remains susceptible to azithromycin and carbapenems; more than 120 infections in US residents were documented through 2023, including patients with no international travel in the previous 30 days. ^[2] Ceftriaxone resistance has also been seen in travellers returning from Iraq, and azithromycin resistance has been identified in isolates from Bangladesh, Cambodia, India, Nepal, Pakistan, Saudi Arabia and the United States. ^[2] For XDR Typhi that fails to respond to a carbapenem alone, one approach is to add a second drug such as azithromycin, although evidence is largely case-based. ^[2]

Typical regimens are summarised below; always check the local formulary and the isolate's susceptibility before finalising treatment.

For nalidixic-acid-resistant strains, a higher ciprofloxacin dose of 10 mg/kg twice daily for 10 days has been used, or ofloxacin 10 to 15 mg/kg divided twice daily for 7 to 10 days, although resistance increasingly makes fluoroquinolones unreliable. ^[5]

Fever often persists for 3 to 5 days after starting effective antibiotics, with a falling maximum temperature each day; if there is no improvement after 5 days, reconsider the diagnosis and drug, and look for a persistent focus such as an abscess or deep-seated infection. ^[2][5]

The best-supported oral paediatric regimen comes from a randomised trial: azithromycin 20 mg/kg per day, maximum 1 g per day, or ceftriaxone 75 mg/kg/day, maximum 2.5 g/day, for 5 days both produced high cure rates in children and adolescents with uncomplicated disease, with no relapse in the azithromycin group. ^[6] In South Asian outpatient trials, cefixime 20 mg/kg/day combined with azithromycin 20 mg/kg/day for 7 days is being studied against azithromycin alone for uncomplicated disease. ^[7]

Most patients recover as outpatients. Hospital admission is appropriate for:

• sepsis, shock, delirium, or inability to take oral medication;
• suspected intestinal bleeding or perforation;
• pregnancy with severe disease;
• complications such as dehydration, hepatitis or pneumonia.
• Intensified monitoring and, for severe toxæmia with shock or altered mental status, dexamethasone. ^[4][5]

Surgical need arises mainly from intestinal perforation and, less often, from uncontrolled bleeding or an intra-abdominal abscess. One comparative surgical study found that segmental resection with anastomosis had the lowest re-perforation and mortality rates for typhoid perforation, although simple closure is also used. ^[5]

• Step down from intravenous to oral therapy once the patient is stable, using susceptibility results to guide the choice. ^[3]
• Repeat culture or reassessment if fever persists beyond 5 days. ^[2]
• Relapse occurs in up to 10% of patients (5 to 10% of chloramphenicol-treated patients; generally 5 to 10% of all patients), usually 1 to 3 weeks after the first episode and often milder. Treat with the same agent, unless resistance is now known. ^{[2][4] [1]}
• Clearance of shedding: most patients continue to shed for days after starting antibiotics, up to 10% for up to 3 months, and between 1% and 4% meet the definition of chronic carrier at one year. ^[4]
• Public-health obligations matter: report the case, and follow local guidance on stool culture and return to work, school or child care, particularly for food handlers and health workers. ^[3][5]

Complications occur in 10 to 15% of hospitalised patients, most often in those ill for more than two weeks. ^[4][2]

Untreated disease can last about a month and historically carried a case fatality of 10 to 30%. With effective antibiotics, case fatality usually falls to under 1%, although some settings report 30 to 50% when disease is severe and treatment delayed. Paratyphoid fever is usually less severe, with a case fatality roughly half that of typhoid, although S. Paratyphi A can match S. Typhi in severity. ^[4][2]

A chronic (typhoid) carrier is a person who continues to excrete S. Typhi in stool or urine for more than one year. Between 1 and 4% of treated patients still excrete the organism at 3 months and are unlikely to stop; about one quarter of carriers give no history of acute typhoid, and shedding can be intermittent, so at least three negative stool cultures are needed to declare someone free of infection. ^{[4][2] [1][5]}

Carriage is more common in women over 40 years of age and in people with gallbladder disease; in the Far East, biliary and urinary carriage are linked with opisthorchiasis and schistosomiasis respectively. Chronic S. Typhi carriers have an increased risk of gallbladder carcinoma. ^[4]

Detection relies on serial stool (and sometimes urine) culture; Vi IgG antibody testing can be useful in outbreak investigation but is less reliable in endemic areas or where Vi vaccine has been used. ^[4]

Carriers are treated with a prolonged course (typically 6 weeks, sometimes up to 12) using agents to which the isolate is susceptible. One review lists amoxicillin with probenecid for 6 to 12 weeks, trimethoprim-sulfamethoxazole for 6 to 12 weeks, and ciprofloxacin or norfloxacin for 4 weeks for adults. Quinolones are usually the most effective option. ^[5]

Cholecystectomy eliminates the carrier state in about 85% of people with gallstones or chronic cholecystitis, but surgery is generally reserved for those whose profession is incompatible with carriage, such as food handlers and healthcare workers. ^[5] Household members of a carrier may be advised to be vaccinated, and in a child or young person a carrier state should prompt a search for an anatomical abnormality. ^[4][5]

Children are uncommonly carriers, so routine post-illness screening is not recommended. ^[5] IDSA guidance adds that asymptomatic people found to excrete S. Typhi in stool may be treated empirically to reduce transmission, particularly when they live or work in high-risk settings. ^[3]

The same measures that control other faecal-oral infection are the backbone of prevention: safe drinking water, separation of human waste from food, handwashing before eating and after toilet use, and safe food handling. These are what drove typhoid to near-eradication in high-income countries, and vaccination is an adjunct. ^[4][2]

There are three kinds of vaccine, and none of them is fully protective:

• Vi capsular polysaccharide (ViCPS), given as a single 0.5 mL intramuscular injection, licensed from 2 years of age, with a booster every 2 years in continued risk. ^[1][2]
• Ty21a, a live attenuated oral vaccine given as 4 capsules, one every other day, licensed from 6 years of age (2 years in some countries), with a booster every 5 years; capsules must be kept refrigerated, taken with cool water, and completed at least one week before exposure; avoid antibiotics within 72 hours. ^[1][2]
• Typhoid conjugate vaccines (TCV), now four prequalified by WHO as of April 2025, are being introduced into childhood programmes in endemic countries. They are more immunogenic in young children and provide longer protection than unconjugated Vi polysaccharide, but are not yet licensed or available in the United States. ^[2][4]

Taken together, the older vaccines protect roughly 50 to 80% of recipients, and natural exposure can overwhelm vaccine-induced immunity, so all travellers should follow food and water precautions even when vaccinated. ^[2] In a Cochrane review, cumulative three-year protection was estimated at 48% for Ty21a and 55% for Vi polysaccharide; the earliest conjugate, Vi-rEPA, reached 91.5% in Vietnamese children. ^[4] ACIP recommends typhoid vaccine for travellers aged 2 years and older going to areas of recognised risk, for microbiologists routinely handling S. Typhi, and for people with intimate exposure to a chronic carrier. ^[1][3]

There is no licensed paratyphoid vaccine, although Ty21a may give limited cross-protection against S. Paratyphi B, and bivalent TCVs targeting S. Paratyphi A are in development. ^[2][4]

Case finding, contact tracing and carrier detection among food handlers and health workers are the remaining tools. In a documented typhoid carrier, household contacts may be vaccinated and the carrier treated or, in selected cases, offered surgery. ^[3][5]

• Children. Diarrhoea and vomiting are more common; complications of meningitis, nephritis and febrile convulsions occur more often. Differences do not change the basic approach, but weight-based dosing and oral hydration need more care. ^[4]
• Pregnancy. Typhoid can cause miscarriage or, rarely, neonatal infection, but treatment mitigates this; azithromycin and cephalosporins are generally compatible and preferable, whereas aminoglycosides, sulphonamides and tetracyclines should be avoided if possible; discuss drug choice with obstetric and infectious-disease teams. ^[4][5]
• Immunocompromise. The differential widens and presentation may be atypical; susceptibility testing is essential; extended courses and suppression may be needed for recurrent salmonellosis. ^[3][4]
• Older adults and women over 40 carry a higher risk of chronic carriage, so persistent shedding should be investigated for gallbladder disease. ^[4]

1. Make the diagnosis clinically first. A gradual fever rising over days in a traveller from or resident of an endemic area, possibly with hepatosplenomegaly and a doughy abdomen, is enough to start treatment while seeking culture. ^[2]
2. Blood culture is the preferred confirmatory test, but where unavailable, samples can be transported and bone marrow or duodenal string sampling reserved for the hardest cases. ^[2][5]
3. The Widal test is cheap and widely used, but it is unreliable; a single positive test should never override a good clinical impression. ^[2]
4. Choose an empiric antibiotic by what is locally effective, not by defaulting to a fluoroquinolone in a high-resistance area. Azithromycin is often the safest oral starting point where resources are limited. ^[1][2]
5. Most patients can be managed as outpatients with oral therapy, hydration, nutrition and close follow-up; refer early for complications requiring surgery. ^[5]
6. Ensure access to surgical management of perforation, which needs a team experienced in abdominal sepsis. ^[5]

• Enteric fever is a human-only systemic bacteraemic illness caused by S. Typhi or S. Paratyphi; it is not simple diarrhoea.
• Global burden is high (around 9.2 million typhoid and 3.8 million paratyphoid cases with 133,000 deaths a year by recent CDC estimates, older estimates are higher), concentrated in south Asia and Africa.
• Incubation is typically 6 to 30 days (range 3 to 60); fever usually reaches 39 to 40 degrees Celsius within the first few days and the illness lasts about a month if untreated.
• Rose spots occur in 1 to 30% of cases; relative bradycardia is unreliable; rigors are uncommon and point towards malaria.
• Complications occur in 10 to 15% of hospitalised patients, typically after 2 weeks: gastrointestinal bleeding (up to 10%) and perforation (1 to 3%) are the dangerous ones. ^[2][4]
• Case fatality historically 10 to 30%; under 1% with prompt, effective antibiotics.
• Blood culture is positive in roughly 50% (single sample) and bone marrow in 80 to 90%; Widal serology should not be used for acute diagnosis.
• Empiric choice follows travel and local resistance: azithromycin, or carbapenem if complicated or XDR likely; ceftriaxone and azithromycin for most other origins; do not start fluoroquinolones empirically in high-resistance settings.
• Fever typically settles within 3 to 5 days; reassess if it has not, and look for a persistent focus.
• Chronic carriage (1 to 4%) is commoner in women over 40 and in gallbladder disease; treatment is prolonged and cholecystectomy helps in selected people.
• Vaccines (ViCPS, Ty21a, and now conjugate vaccines) protect roughly 50 to 80%; no paratyphoid vaccine is licensed.
• Enteric fever is notifiable in many countries; household contacts and food handlers need public-health follow-up.

Malaria; dengue; infectious diarrhoea and foodborne illness; acute abdomen and intestinal obstruction; acute kidney injury; infective endocarditis; E. coli infection; traveller's health and immunisation; gallbladder disease and cholecystitis.