Issue: June 2020
Disclosures: Kaye reports no relevant financial disclosures.
June 22, 2020
7 min read

Typhoid fever, paratyphoid fever and the emergence of XDR typhoid fever

Issue: June 2020
Disclosures: Kaye reports no relevant financial disclosures.
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Typhoid fever and paratyphoid fever are clinically indistinguishable and produce the syndrome known as enteric fever. Both are caused by Salmonella that infect only humans. Therefore, when the diagnosis of typhoid or paratyphoid fever is made, the origin is another human.

Paratyphoid fever is generally less severe than typhoid fever. The cause of typhoid fever is Salmonella enterica serovar Typhi (S. Typhi for short). The cause of paratyphoid fever is Salmonella enterica serovar Paratyphi (S. Paratyphi for short). There are three S. Paratyphispecies: A, B and C; C is rare. Worldwide, there are 11 to 21 million cases of typhoid fever annually with about 150,000 deaths. There are about 6 million cases of paratyphoid cases annually, with about 50,000 deaths. Without treatment, the case fatality rate of typhoid fever is about 20%, but with appropriate treatment, it drops to less than 5%. In developing countries with poor sanitation, where enteric fever is endemic, mainly children and young adults are affected. The age is older in those with enteric fever occurring in industrialized countries, where mainly travelers to endemic areas become infected.

The recent development of large outbreaks (thousands of cases) of extensively drug-resistant (XDR) typhoid fever in Pakistan has complicated the approach to the treatment of typhoid fever.

Donald Kaye
Donald Kaye

Epidemiology in the United States

About 350 cases of typhoid fever and 90 cases of paratyphoid fever are diagnosed yearly in the U.S. The CDC estimates that the actual number of those infected with S. Typhi in the U.S. annually is about 5,700. Most of these infections are related to travel to areas where these diseases are prevalent and sanitation is poor. There have been cases of XDR typhoid imported into the U.S. from Pakistan. A minority of cases in the U.S. and other industrialized countries are acquired from people who have the acute disease or are convalescent or are chronic carriers of the organism.

Infection occurs from ingestion of the bacteria in food or water contaminated with the feces or occasionally urine of people with the disease or those who have recovered from the disease but are carriers of the bacteria.


Salmonella are motile, non-spore-forming, gram-negative facultative anaerobic bacteria. They are intracellular pathogens. After ingestion of S. Typhi or Paratyphi, the organism invades the mononuclear phagocytes in Peyer’s patches in the ileum and in mesenteric lymph nodes. They multiply intracellularly and then are carried through the lymphatic system and the bloodstream to the liver, spleen, bone marrow and other parts of the reticuloendothelial system, where they multiply intracellularly in mononuclear phagocytes. The onset of illness with fever is related to the bacteremia and release of cytokines from mononuclear phagocytes. Ulceration over Peyer’s patches accounts for the abdominal pain and the occasional complications of bleeding and intestinal perforation that may occur.


Gastric acid serves as a defense mechanism by reducing the effective inoculum of Salmonella reaching the small intestine. Achlorhydria produced by disease, surgery, age or drugs increases susceptibility to Salmonella infection.

Symptoms, signs and laboratory findings

After an incubation period that is generally 1 to 2 weeks for typhoid fever and 1 to 10 days for paratyphoid fever, there is onset of fever that starts low and staircases upward over a period of days. The fever tends to be sustained without much variation throughout the day; this changes if the patient is given antipyretics and can result in spiking fever with wide swings of temperature and shaking chills. The temperature often plateaus at 104°F or higher. In up to half of the patients, there is relative bradycardia despite the high fever. There is abdominal pain and distention. Headache is frequent, and apathy, confusion, delirium and even psychosis may be seen. There is often a nonproductive cough. In about 30% of patients, an erythematous maculopapular rash may appear on the abdomen or lower chest, consisting of a few 2-mm to 5-mm erythematous lesions (rose spots). These are difficult to see in dark-skinned individuals. The rash tends to appear 2 to 3 weeks into the illness. Hepatosplenomegaly develops after 2 weeks of illness. Diarrhea may occur but is not a prominent part of the disease. In fact, the patient is often constipated. The complications of intestinal hemorrhage or perforation are seen in about 5% of untreated patients; these occur after 2 weeks of illness. The whole illness, if untreated, lasts for about 4 weeks.

Patients with enteric fever are usually anemic. The peripheral white blood cell count is usually normal, but about 20% may be leukopenic. If leukocytosis occurs after 2 weeks of illness, intestinal perforation should be suspected. Liver chemistries are frequently abnormal and may suggest viral hepatitis.

Relapse can occur in up to 10% of patients, usually about 1 to 3 weeks after resolution of fever. Relapses are generally milder than the original episode. Antibiotic therapy, even if inadequate, can significantly alter the course of enteric fever and its manifestations.


Prolonged fever combined with abdominal pain and distention in a person living in an endemic area or in a traveler who has been in an endemic area should suggest the possibility of enteric fever. Relative bradycardia and leukopenia should add to the suspicion. Isolation of the infecting bacteria is the major method of diagnosis. Blood cultures are positive in most patients if multiple cultures are taken with large volumes of blood. The time in the course of illness that blood cultures are taken is an important determinant of positivity. During the first week of illness, the yield is as high as 90%, whereas during the third week it drops to less than half. Although bone marrow cultures are more sensitive, they are invasive and not needed in most patients. Stool cultures are usually negative for S. Typhiduring the first week of illness but by the third week generally turn positive. After recovery, stool cultures become negative in the vast majority of patients over a period of months. However, about 1% of untreated patients become long-term carriers, usually related to localization of S. Typhi in the gall bladder. Long-term carriers can excrete S. Typhi for life. This is especially likely to happen with the presence of gallstones.


The Widal test is a commonly used serological test that measures antibodies to the S. Typhi surface polysaccharide antigens (O antigens) and to the flagellar antigens (H antigens). A high titer in an endemic area may just indicate a previous infection. Furthermore, because of cross-reactivity with other Salmonella and even some other gram-negative bacilli, a high titer is not specific for S. Typhi. A fourfold rise in titer comparing acute to convalescent serum is evidence for typhoid fever but occurs too late to be of help in most cases.


Many strains of S. Typhiare resistant to the antibiotics that have classically been used for treatment such as ampicillin, trimethoprim/sulfamethoxazole, and outside of the U.S., chloramphenicol. The fluoroquinolones such as ciprofloxacin or ofloxacin emerged as drugs of choice in typhoid fever, along with third-generation cephalosporins (eg, ceftriaxone), and probably still are drugs of choice, provided the strain being treated is susceptible. The emergence of S. Typhiresistant to the fluoroquinolones has complicated the issue. Even more concerning is the outbreak of XDR typhoid fever in Pakistan (resistant to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, ciprofloxacin and ceftriaxone). The drugs of choice for treating these XDR infections are azithromycin for the milder cases and carbapenems for the more severe cases.

Some of these cases have been detected in travelers returning to the U.S. and the United Kingdom. Patients with typhoid fever acquired in South Asia should be assumed to have XDR typhoid fever. Azithromycin dosage for these adult patients should be 1,000 mg orally once, then 500 mg orally daily, or 1,000 mg orally once daily for at least 5 to 7 days. Carbapenems should be used for patients with suspected severe or complicated typhoid fever who have traveled to South Asia, especially Pakistan. Once susceptibility tests have been completed, treatment can be altered accordingly.

Response of fever to treatment is usually slow and takes several days. Corticosteroid therapy has been added to antibiotics in severely ill patients (shock or obtunded patients) with apparently reduced mortality.

The mortality rate of treated enteric fever is less than 1%.

There is little clinical significance of long-term carriage of S. Typhi for the carrier, as long as they do not work as food handlers and wash their hands well before preparing food for others. Long-term carriers as defined by excretion of S. Typhi in stools for longer than 1 year have been treated successfully with prolonged courses of antibiotics and even cholecystectomy (when there are gallstones present and antibiotics alone are not successful). Fluoroquinolones are the agents of choice if the S. Typhi strain is susceptible.


Prevention in the traveler

In endemic areas for enteric fever, drinking of untreated water or use of ice cubes from untreated water should be avoided. Similarly, all food should be cooked and fruit peeled.

In addition, there are two vaccines that are at best 80% effective and should be given for travelers to an endemic area. One is Ty21a (Vivotif), a live-attenuated vaccine taken orally every other day for four doses. It needs a booster every 5 years. The other is ViCPS (Typhim Vi), a Vi polysaccharide vaccine that is injected and requires a booster every 2 years.

There is no vaccine available for paratyphoid fever.