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Background
Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella typhi. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications. S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War.[1] The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.[2]

Transmission
S typhi has no nonhuman vectors. The following are modes of transmission:

Oral transmission via food or beverages handled by an individual who chronically sheds the bacteria through stool or, less commonly, urine Hand-to-mouth transmission after using a contaminated toilet and neglecting hand hygiene Oral transmission via sewage-contaminated water or shellfish (especially in the developing world)[3]

An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy volunteers.[4]

Pathophysiology
All pathogenic Salmonella species are engulfed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal salmonellae are phagocytized throughout the distal ilium and colon. With toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing inflammation and suppressing the infection.[5, 6] In contrast to the nontyphoidal salmonellae, S typhi enters the host's system primarily through the distal ilium. S typhi has specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ilium (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. S typhi has a Vi capsular antigen that masks PAMPs,

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avoiding neutrophil-based inflammation. The bacteria then induce their host macrophages to attract more macrophages.[5] It co-opts the macrophages' cellular machinery for their own reproduction[7] as it is carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, the S typhi bacteria pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body.[6] The gallbladder is then infected via either bacteremia or direct extension of S typhi infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts.[6, 2]

Life cycle of Salmonella typhi.

Risk factors
S typhi are able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S typhi infection.[6] HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection; however, the data and opinions in the literature as to whether this is true for S typhi infection are conflicting. If an association exists, it is probably minor.[8, 9, 10, 11] Other risk factors for clinical S typhi infection include various genetic polymorphisms. These risk factors often also predispose to other intracellular pathogens. For instance, PARK2 and PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling molecules that dampen the macrophage response. Polymorphisms in their shared regulatory region are found disproportionately in persons infected with Mycobacterium leprae and S typhi.[12] On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del, which is associated with a decreased susceptibility to typhoid fever, as well as to cholera and tuberculosis. The homozygous F508del mutation in CFTR is associated with cystic fibrosis.

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Thus, typhoid fever may contribute to evolutionary pressure that maintains a steady occurrence of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.[13, 14] Environmental and behavioral risk factors that are independently associated with typhoid fever include eating food from street vendors, living in the same household with someone who has new case of typhoid fever, washing the hands inadequately, sharing food from the same plate, drinking unpurified water, and living in a household that does not have a toilet.[15, 12] As the middle class in south Asia grows, some hospitals there are seeing a large number of typhoid fever cases among relatively well-off university students who live in group households with poor hygeine.[16] American clinicians should keep this in mind, as members of this cohort often come to the United States for higher degrees.

Epidemiology
Frequency
United States Since 1900, improved sanitation and successful antibiotic treatment have steadily decreased the incidence of typhoid fever in the United States. In 1920, 35,994 cases of typhoid fever were reported. In 2006, there were 314. Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had been outside of the country within the preceding 30 days. Two thirds of these individuals had just journeyed from the Indian subcontinent. The 3 known outbreaks of typhoid fever within the United States were traced to imported food or to a food handler from an endemic region. Remarkably, only 17% of cases acquired domestically were traced to a carrier.[17] International Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but 80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or Vietnam.[18] Within those countries, typhoid fever is most common in underdeveloped areas. Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and kills an estimated 200,000 people every year.[19] In the United States, most cases of typhoid fever arise in international travelers. The average yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of departure was as follows:[17]

Canada - 0 Western Hemisphere outside Canada/United States - 1.3 Africa - 7.6 Asia - 10.5 India - 89 (122 in 2006) Total (for all countries except Canada/United States) - 2.2

Mortality/Morbidity

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With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and a 0.2% risk of mortality.[17] Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity often involving the central nervous system. The case fatality rate in the United States in the pre-antibiotic era was 9%-13%.[20]

Race
Typhoid fever has no racial predilection.

Sex
Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006 involved males.[17]

Age
Most documented typhoid fever cases involve school-aged children and young adults. However, the true incidence among very young children and infants is thought to be higher. The presentations in these age groups may be atypical, ranging from a mild febrile illness to severe convulsions, and the S typhi infection may go unrecognized. This may account for conflicting reports in the literature that this group has either a very high or a very low rate of morbidity and mortality

History
A severe nonspecific febrile illness in a patient who has been exposed to S typhi should always raise the diagnostic possibility of typhoid fever (enteric fever).

Classic typhoid fever syndrome

Typhoid fever begins 7-14 days after ingestion of S typhi. The fever pattern is stepwise, characterized by a rising temperature over the course of each day that drops by the subsequent morning. The peaks and troughs rise progressively over time. Over the course of the first week of illness, the notorious gastrointestinal manifestations of the disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that lasts the duration of the illness. The individual then develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise.[2] At approximately the end of the first week of illness, the fever plateaus at 103-104F (3940C). The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days.[2] These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or nontyphoidal salmonellosis.[22]

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During the second week of illness, the signs and symptoms listed above progress. The abdomen becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse (double beat, the second beat weaker than the first) may develop. In the third week, the still febrile individual grows more toxic and anorexic with significant weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and crackles over the lung bases. Abdominal distension is severe. Some patients experience foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. This complication is often unheralded and may be masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal hemorrhage may cause death. If the individual survives to the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days. Intestinal and neurologic complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Some survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely.[16, 23, 24, 2, 6]

Various presentations of typhoid fever

The clinical course of a given individual with typhoid fever may deviate from the above description of classic disease. The timing of the symptoms and host response may vary based on geographic region, race factors, and the infecting bacterial strain. The stepladder fever pattern that was once the hallmark of typhoid fever now occurs in as few as 12% of cases. In most contemporary presentations of typhoid fever, the fever has a steady insidious onset. Young children, individuals with AIDS, and one third of immunocompetent adults who develop typhoid fever develop diarrhea rather than constipation. In addition, in some localities, typhoid fever is generally more apt to cause diarrhea than constipation. Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or fever alone. Some patients, especially in India and Africa, present primarily with neurologic manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or Guillain-Barr syndrome. Other unusual complications include pancreatitis,[25] meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body.[2] Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever[2, 26, 27, 28, 29, 30] (Open Table in a new window)
Incubation Week 1 Systemic Stepladder fever pattern or insidious onset fever Very Very common a common Week 2 Week 3 Week 4 Recovery phase or death (15% of untreated Post 10%-20% relapse; 3%4% chronic carriers;

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Acute high fever Chills Rigors Anorexia Diaphoresis Neurologic Malaise Insomnia

Very rareb Almost allc Uncommon Almost all Very common

cases)

long-term neurologic sequelae (extremely rare); gallbladder cancer (RR=167; carriers)

Almost all Almost all Typhoid state Very (common) common Commond Very common Very rare Very rare Very common Common

Confusion/delirium

Psychosis Catatonia Frontal headache (usually mild) Meningeal signs Parkinsonism Ear, nose, and throat Coated tongue

Raree Very rare

Rare

Very common

Sore throatf Pulmonary Mild cough Bronchitic cough Rales Common Common Common

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Pneumonia

Rare (lobar)

Rare

Common (basal)

Cardiovascular Dicrotic pulse Myocarditis Pericarditis Rare Rare Extremely rareg Very rare Common

Thrombophlebitis Gastrointestinal Constipation Very common Rare Very common (84%)[30] Very common Rare Common

Diarrhea Bloating with tympany

Common (pea soup)

Diffuse mild abdominal pain Sharp right lower quadrant pain Gastrointestinal hemorrhage

Very rare; Very common usually trace Rare

intestinal perforation Hepatosplenomegaly Jaundice Gallbladder pain Urogenital Urinary retention Common Common Common Very rare

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Hematuria Renal pain Musculoskeletal Myalgias Arthralgias Rheumatologic Arthritis (large joint) Dermatologic Rose spots Miscellaneous Abscess (anywhere) Very rare Very rare

Rare Rare

Extremely rare

Rare

Extremely Extremely Extremely rare rare rare

Very common: Symptoms occur in well over half of cases (approximately 65%-95%). Very rare: Symptoms occur in less than 5% of cases. Almost all: Symptoms occur in almost all cases. Common: Symptoms occur in 35%-65% of cases. Rare: Symptoms occur in 5%-35% of cases. Blank cells: No mention of the symptom at that phase was found in the literature. Extremely rare: Symptoms have been described in occasional case reports.

If appropriate treatment is initiated within the first few days of full-blown illness, the disease begins to remit after about 2 days, and the patient's condition markedly improves within 4-5 days. Any delay in treatment increases the likelihood of complications and recovery time.

Causes
S typhi and Salmonella paratyphi cause typhoid fever.

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Treated typhoid fever

Differentials

Abdominal Abscess Amebic Hepatic Abscesses Appendicitis Brucellosis Dengue Fever Influenza Leishmaniasis Malaria Rickettsial diseases Toxoplasmosis Tuberculosis Tularemia Typhus

aboratory Studies
The diagnosis of typhoid fever (enteric fever) is primarily clinical. Importantly, the reported sensitivities of tests for S typhi vary greatly in the literature, even among the most recent articles and respected journals.

Culture
o o

o o

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The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are widely considered 100% specific. Culture of bone marrow aspirate is 90% sensitive until at least 5 days after commencement of antibiotics. However, this technique is extremely painful, which may outweigh its benefit.[31] Blood, intestinal secretions (vomitus or duodenal aspirate), and stool culture results are positive for S typhi in approximately 85%-90% of patients with typhoid fever who present within the first week of onset. They decline to 20%-30% later in the disease course. In particular, stool culture may be positive for S typhi several days after ingestion of the bacteria secondary to inflammation of the intraluminal dendritic cells. Later in the illness, stool culture results are positive because of bacteria shed through the gallbladder. Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Large-volume (10-30 mL) blood culture and clot culture may increase the likelihood of detection.[32] Stool culture alone yields a sensitivity of less than 50%, and urine culture alone is even less sensitive. Cultures of punch-biopsy samples of rose spots reportedly yield a sensitivity of 63% and may show positive results even after administration of antibiotics. A single rectal swab culture upon hospital admission can be expected to detect S typhi in 30%-40% of patients. S typhi has also been isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes, resected intestine, pharynx, tonsils, abscess, and bone, among others. Bone marrow aspiration and blood are cultured in a selective medium (eg, 10% aqueous oxgall) or a nutritious medium (eg, tryptic soy broth) and are incubated at 37C for at least 7 days. Subcultures are made daily to one selective medium (eg, MacConkey agar) and one inhibitory medium (eg, Salmonella-Shigella agar).

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Identification of the organism with these conventional culture techniques usually takes 48-72 hours from acquisition.

Table 2. Sensitivities of Cultures[2, 32, 33, 34] (Open Table in a new window)
Incubation Week 1 Bone marrow aspirate (0.5-1 mL) Week 2 Week 3 Week 4

90% (may decrease after 5 d of antibiotics) 40%-80% ~20% Variable (20%-60%)

Blood (10-30 mL), stool, or duodenal aspirate culture Urine

25%-30%, timing unpredictable

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Polymerase chain reaction (PCR):[35, 36] PCR has been used for the diagnosis of typhoid fever with varying success. Nested PCR, which involves two rounds of PCR using two primers with different sequences within the H1-d flagellin gene of S typhi, offers the best sensitivity and specificity. Combining assays of blood and urine, this technique has achieved a sensitivity of 82.7% and reported specificity of 100%. However, no type of PCR is widely available for the clinical diagnosis of typhoid fever. Specific serologic tests o Assays that identify Salmonella antibodies or antigens support the diagnosis of typhoid fever, but these results should be confirmed with cultures or DNA evidence. o The Widal test was the mainstay of typhoid fever diagnosis for decades. It is used to measure agglutinating antibodies against H and O antigens of S typhi. Neither sensitive nor specific, the Widal test is no longer an acceptable clinical method. o Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect enzymelinked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide, as well as monoclonal antibodies against S typhi flagellin,[37] are promising, but the success rates of these assays vary greatly in the literature. Other nonspecific laboratory studies o Most patients with typhoid fever are moderately anemic, have an elevated erythrocyte sedimentation rate (ESR), thrombocytopenia, and relative lymphopenia. o Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) and decreased fibrinogen levels. o Circulating fibrin degradation products commonly rise to levels seen in subclinical disseminated intravascular coagulation (DIC). o Liver transaminase and serum bilirubin values usually rise to twice the reference range. o Mild hyponatremia and hypokalemia are common. o A serum alanine amino transferase (ALT)tolactate dehydrogenase (LDH) ratio of more than 9:1 appears to be helpful in distinguishing typhoid from viral hepatitis. A ratio of greater than 9:1 supports a diagnosis of acute viral hepatitis, while ratio of less than 9:1 supports typhoid hepatitis.

Radiography: Radiography of the kidneys, ureters, and bladder (KUB) is useful if bowel perforation (symptomatic or asymptomatic) is suspected. CT scanning and MRI: These studies may be warranted to investigate for abscesses in the liver or bones, among other sites.

Procedures

Bone marrow aspiration: The most sensitive method of isolating S typhi is BMA culture (see Lab Studies).

Histologic Findings
The hallmark histologic finding in typhoid fever is infiltration of tissues by macrophages (typhoid cells) that contain bacteria, erythrocytes, and degenerated lymphocytes. Aggregates of these macrophages are called typhoid nodules, which are found most commonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow but may be found in the kidneys, testes, and parotid glands. In the intestines, 4 classic pathologic stages occur in the course of infection: (1) hyperplastic changes, (2) necrosis of the intestinal mucosa, (3) sloughing of the mucosa, and (4) the development of ulcers. The ulcers may perforate into the peritoneal cavity. In the mesenteric lymph nodes, the sinusoids are enlarged and distended by large collections of macrophages and reticuloendothelial cells. The spleen is enlarged, red, soft, and congested; its serosal surface may have a fibrinous exudate. Microscopically, the red pulp is congested and contains typhoid nodules. The gallbladder is hyperemic and may show evidence of cholecystitis. Liver biopsy specimens from patients with typhoid fever often show cloudy swelling, balloon degeneration with vacuolation of hepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli can be observed at these sites.[2, 6]

Staging
The proper treatment approach to typhoid fever depends on whether the illness is complicated or uncomplicated. Complicated typhoid fever is characterized by melena (3% of all hospitalized patients with typhoid fever), serious abdominal discomfort, intestinal perforation, marked neuropsychiatric symptoms, or other severe manifestations. Depending on the adequacy of diagnosis and treatment, complicated disease may develop in up to 10% of treated patients. Delirium, obtundation, stupor, coma, or shock demands a particularly aggressive approach (see Treatment).[29]

Medical Care
If a patient presents with unexplained symptoms described in Table 1 within 60 days of returning from an typhoid fever (enteric fever) endemic area or following consumption of food prepared by an individual who is known to carry typhoid, broad-spectrum empiric antibiotics should be started immediately. Treatment should not be delayed for confirmatory tests since prompt treatment drastically reduces the risk of complications and fatalities. Antibiotic therapy should be narrowed once more information is available.

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Compliant patients with uncomplicated disease may be treated on an outpatient basis. They must be advised to use strict handwashing techniques and to avoid preparing food for others during the illness course. Hospitalized patients should be placed in contact isolation during the acute phase of the infection. Feces and urine must be disposed of safely.

Surgical Care
Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Small-bowel resection is indicated for patients with multiple perforations. If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is not always successful in eradicating the carrier state because of persisting hepatic infection.

Consultations
An infectious disease specialist should be consulted. Consultation with a surgeon is indicated upon suspected gastrointestinal perforation, serious gastrointestinal hemorrhage, cholecystitis, or extraintestinal complications (arteritis, endocarditis, organ abscesses).

Diet
Fluids and electrolytes should be monitored and replaced diligently. Oral nutrition with a soft digestible diet is preferable in the absence of abdominal distension or ileus.

Activity
No specific limitations on activity are indicated for patients with typhoid fever. As with most systemic diseases, rest is helpful, but mobility should be maintained if tolerable. The patient should be encouraged to stay home from work until recovery.

Antibiotics
Class Summary

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Until susceptibilities are determined, antibiotics should be empiric, for which there are various recommendations. The authors of this article consider the 2003 World Health Organization (WHO) guidelines to be outdated. These recommend fluoroquinolone treatment for both complicated and uncomplicated cases of typhoid fever, but 38% of S typhi isolates taken in the United States in 2006 were fluoroquinolone resistant (nalidixic acidresistant S typhi [NARST]), and the rate of multidrug resistance was 13%. (Multidrug-resistant S typhi

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Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. As a general principle of antimicrobial treatment, intermediate susceptibility should be regarded as equivalent to resistance. Between 1999 and 2006, 13% of S typhi isolates collected in the United States were multidrug resistant.

is, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole.) The particular sensitivity pattern of the organism in its area of acquisition should be the major basis of empiric antibiotic choice. It may soon become necessary to treat all cases presumptively for multidrug resistance until sensitivities are obtained. Note that nalidixic acid is a nontherapeutic drug that is used outside of the United States as a stand-in for fluoroquinolones in sensitivity assays. In the United States, it is still used specifically for S typhi infection.[39, 17]

History of antibiotic resistance

Chloramphenicol was used universally to treat typhoid fever from 1948 until the 1970s, when widespread resistance occurred. Ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ) then became treatments of choice. However, in the late 1980s, some S typhi and S paratyphi strains (multidrug resistant [MDR] S typhi or S paratyphi) developed simultaneous plasmidmediated resistance to all three of these agents. Fluoroquinolones are now recommended by most authorities for the treatment of typhoid fever. They are highly effective against susceptible organisms, yielding a better cure rate than cephalosporins. Unfortunately, resistance to first-generation fluoroquinolones is widespread in many parts of Asia. In recent years, third-generation cephalosporins have been used in regions with high fluoroquinolone resistance rates, particularly in south Asia and Vietnam. Unfortunately, sporadic resistance has been reported, so it is expected that these will become less useful over time.[39]

Mechanisms of antibiotic resistance

The genes for antibiotic resistance in S typhi and S paratyphi are acquired from Escherichia coli and other gram-negative bacteria via plasmids. The plasmids contain cassettes of resistance genes that are incorporated into a region of the Salmonella genome called an integron. Some plasmids carry multiple cassettes and immediately confer resistance to multiple classes of antibiotics. This explains the sudden appearance of MDR strains of S typhi and S paratyphi, often without intermediate strains that have less-extensive resistance. The initial strains of antibiotic-resistant S typhi and S paratyphi carried chloramphenicol acetyltransferase type I, which encodes an enzyme that inactivates chloramphenicol via acetylation. MDR strains may carry dihydrofolate reductase type VII, which confers resistance to trimethoprim. Interestingly, in areas where these drugs have fallen out of use, S typhi has reverted to wild type, and they are often more effective than newer agents.[40, 41, 42,
30]

Resistance to fluoroquinolones is evolving in an ominous direction. Fluoroquinolones target DNA gyrase and topoisomerase IV, bacterial enzymes that are part of a complex that uncoils and recoils bacterial DNA for transcription.[43]S typhi most commonly develops fluoroquinolone resistance through specific mutations in gyrA and parC, which code for the binding region of DNA gyrase and topoisomerase IV, respectively.

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A single point mutation gyrA confers partial resistance. If a second gyrA point mutation is added, the resistance increases somewhat. However, a mutation in parC added to a single gyrA mutation confers full in vitro resistance to first-generation fluoroquinolones. Clinically, these resistant strains show a 36% failure rate when treated with a first-generation fluoroquinolone such as ciprofloxacin.[44] The risk of relapse after bacterial clearance is higher in both partially and fully resistant strains than in fully susceptible strains.[18] The third-generation fluoroquinolone gatifloxacin appears to be highly effective against all known clinical strains of S typhi both in vitro and in vivo. However, any two of a number of gyrA mutations, when added to the parC mutation, confer full in vitro resistance. Although such a combination has yet to be discovered in vivo, all of these mutations exist in clinic strains, and it seems highly likely that a gatifloxacin-resistant strain will be encountered clinically if selective pressure with fluoroquinolones continues to be exerted.[44]

Geography of resistance
Among S typhi isolates obtained in the United States between 1999 and 2006, 43% were resistant to at least one antibiotic. Nearly half of S typhi isolates found in the United States now come from travelers to the Indian subcontinent, where fluoroquinolone resistance is endemic (see Table 3). The rate of fluoroquinolone resistance in south and Southeast Asia and, to some extent, in East Asia is generally high and rising (see Table 3). Susceptibility to chloramphenicol, TMP-SMZ, and ampicillin in these areas is rebounding. In Southeast Asia, MDR strains remain predominant, and some acquired resistance to fluoroquinolones by the early 2000s. The most recent professional guideline for the treatment of typhoid fever in south Asia was issued by the Indian Association of Pediatrics (IAP) in October 2006. Although these guidelines were published for pediatric typhoid fever, the authors feel that they are also applicable to adult cases. For empiric treatment of uncomplicated typhoid fever, the IAP recommends cefixime and, as a second-line agent, azithromycin. For complicated typhoid fever, they recommend ceftriaxone. Aztreonam and imipenem are second-line agents for complicated cases.[45] The authors believe that the IAP recommendations have more validity than the WHO recommendations for empiric treatments of typhoid fever in both adults and children. In high-prevalence areas outside the areas discussed above, the rate of intermediate sensitivity or resistance to fluoroquinolones is 3.7% in the Americas (P =.132), 4.7% (P =.144) in sub-Saharan Africa, and 10.8% (P =.706) in the Middle East. Therefore, for strains that originate outside of south or Southeast Asia, the WHO recommendations may still be validthat uncomplicated disease should be treated empirically with oral ciprofloxacin and complicated typhoid fever from these regions should be treated with intravenous ciprofloxacin.[39, 42, 46, 19, 47] Antibiotic resistance is a moving target. Reports are quickly outdated, and surveys of resistance may have limited geographic scope. Therefore, any recommendation regarding antibiotic treatment must be taken with a grain of salt. In the authors' opinion, if the origin of the infection is unknown, the combination of a first-generation fluoroquinolone and a thirdgeneration cephalosporin should be used.

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Table 3. Antibiotic Recommendations by Origin and Severity (Open Table in a new window)
Location Severity First-Line Antibiotics Second-Line Antibiotics Azithromycin PO

South Asia, East Asia[45]

[48, 40]

Uncomplicated Cefixime PO Complicated

Ceftriaxone IV or Aztreonam IV or Cefotaxime IV Imipenem IV Cefixime PO or Amoxicillin PO or Ofloxacin PO TMP-SMZ PO or Azithromycin PO

Eastern Europe, Middle East, sub-Saharan Uncomplicated Ciprofloxacin PO or Africa, South America[46, 49]

Complicated

Ciprofloxacin IV or Ceftriaxone IV or Ofloxacin IV Cefotaxime IV or Ampicillin IV or TMP-SMZ IV

Unknown geographic origin or Southeast Asia[50, 45]

[48, 40, 46, 49]

Uncomplicated Cefixime PO plus Azithromycin PO* Ciprofloxacin PO or Ofloxacin PO

Cefotaxime IV, plus Ciprofloxacin IV or

Imipenem IV, plus Ciprofloxacin IV or

Ofloxacin IV

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Complicated

Ceftriaxone IV or Aztreonam IV or

Ofloxacin IV *Note that the combination of azithromycin and fluoroquinolones is not recommended because it may cause QT prolongation and is relatively contraindicated.

Future directions
Researchers in Cameroon report that a compound derived from the seeds of Turraeanthus africanus, an African folk remedy for typhoid fever, is active against S typhi in vitro.[51] Perhaps they are on their way to creating an addition to the shrinking arsenal of effective antimicrobials.
View full drug information

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. Since its introduction in 1948, has proven to be remarkably effective for enteric fever worldwide. For sensitive strains, still most widely used antibiotic to treat typhoid fever. In the 1960s, S typh i strains with plasmid-mediated resistance to chloramphenicol began to appear and later became widespread in many endemic countries of the Americas and Southeast Asia, highlighting need for alternative agents. Produces rapid improvement in patient's general condition, followed by defervescence in 3-5 d. Reduced preantibiotic-era case-fatality rates from 10%-15% to 1%-4%. Cures approximately 90% of patients. Administered PO unless patient is nauseous or experiencing diarrhea; in such cases, IV route should be used initially. IM route should be avoided because it may result in unsatisfactory blood levels, delaying defervescence.
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Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. At least as effective as chloramphenicol in rapidity of defervescence and relapse rate. Convalescence carriage occurs less commonly than with other agents when organisms are fully susceptible. Usually given PO with a daily dose of 75-100 mg/kg tid for 14 d.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

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Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa. As effective as chloramphenicol in defervescence and relapse rate. Trimethoprim alone has been effective in small groups of patients.
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Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared. Proven to be highly effective for typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d, and convalescent carriage and relapses are rare. Other quinolones (eg, ofloxacin, norfloxacin, pefloxacin) usually are effective. If vomiting or diarrhea is present, should be given IV. Fluoroquinolones are highly effective against multiresistant strains and have intracellular antibacterial activity. Not currently recommended for use in children and pregnant women because of observed potential for causing cartilage damage in growing animals. However, arthropathy has not been reported in children following use of nalidixic acid (an earlier quinolone known to produce similar joint damage in young animals) or in children with cystic fibrosis, despite high-dose treatment.
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Cefotaxime (Claforan)

Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Excellent in vitro activity against S typhi and other salmonellae and has acceptable efficacy in typhoid fever. Only IV formulations are available. Recently, emergence of domestically acquired ceftriaxone-resistant Salmonella infections has been described.

Azithromycin (Zithromax)

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Treats mild to moderate microbial infections. Administered PO at 10 mg/kg/d (not exceeding 500 mg), appears to be effective to treat uncomplicated typhoid fever in children 4-17 y. Confirmation of these results could provide an alternative for treatment of typhoid fever in children in developing countries, where medical resources are scarce.

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Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum gram-negative activity against grampositive organisms; Excellent in vitro activity against S typhi and other salmonellae.
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Cefoperazone (Cefobid)

Discontinued in the United States. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.
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Ofloxacin (Floxin)

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

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Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

Corticosteroids

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Dexamethasone may decrease the likelihood of mortality in severe typhoid fever cases complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has been definitively ruled out by cerebrospinal fluid studies. To date, the most systematic trial of this has been a randomized controlled study in patients aged 3-56 years with severe typhoid fever who were receiving chloramphenicol therapy. This study compared outcomes in 18 patients given placebo with outcomes in 20 patients given dexamethasone 3 mg/kg IV over 30 minutes followed by dexamethasone 1 mg/kg every 6 hours for 8 doses. The fatality rate in the dexamethasone arm was 10% versus 55.6% in the placebo arm (P =.003).[52]

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Class Summary

Nonetheless, this point is still debated. A 2003 WHO statement endorsed the use of steroids as described above, but reviews by eminent authors in the New England Journal of Medicine (2002)[6] and the British Medical Journal (2006)[53] do not refer to steroids at all. A 1991 trial compared patients treated with 12 doses of dexamethasone 400 mg or 100 mg to a retrospective cohort in whom steroids were not administered. This trial found no difference in outcomes among the groups.[54] The data are sparse, but the authors of this article agree with the WHO that dexamethasone should be used in cases of severe typhoid fever.
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Dexamethasone (Decadron)

Prompt administration of high-dose dexamethasone reduces mortality in patients with severe typhoid fever without increasing incidence of complications, carrier states, or relapse among survivors.

Further Inpatient Care

If treated with well-selected antibiotics, patients with typhoid fever (enteric fever) should defervesce within 3-5 days. However, patients with complicated typhoid fever should finish their course intravenously and should remain in the hospital if unable to manage this at home. Patients with complicated typhoid fever should be admitted through the acute phase of the illness. Uncomplicated cases are generally treated on an outpatient basis unless the patient is a public health risk or cannot be fully monitored outside the home.

Further Outpatient Care

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After discharge, patients should be monitored for relapse or complications for 3 months after treatment has commenced. Five percent to 10% of patients treated with antibiotics experience relapse of typhoid fever after initial recovery. Relapses typically occur approximately 1 week after therapy is discontinued, but relapse after 70 days has been reported. In these cases, the blood culture results are again positive, and high serum levels of H, O, and Vi antibodies and rose spots may reappear. o A relapse of typhoid fever is generally milder and of shorter duration than the initial illness. In rare cases, second or even third relapses occur. Notably, the relapse rate is much lower following treatment with the new quinolone drugs, which have effective intracellular penetration. o S typhi and S paratyphi rarely develop antibiotic resistance during treatment. If an antibiotic has been chosen according to sensitivities, relapse should dictate a search for anatomic, pathologic, or genetic predispositions rather than for an alternate antibiotic. o Previous infection does not confer immunity. In any suspected relapse, infection with a different strain should be ruled out.

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Depending on the antibiotic used, between 0% and 5.9% of treated patients become chronic carriers. In some cases, the organism evades antibiotics by sequestering itself within gallstones or Schistosoma haematobium organisms that are infecting the bladder. From there, it is shed in stool or urine, respectively. If present, these diseases must be cured before the bacterium can be eliminated. Untreated survivors of typhoid fever may shed the bacterium in the feces for up to 3 months. Therefore, after disease resolution, 3 stool cultures in one-month intervals should be performed to rule out a carrier state. Concurrent urinary cultures should be considered.

Deterrence/Prevention

Travelers to endemic countries should avoid raw unpeeled fruits or vegetables since they may have been prepared with contaminated water; in addition, they should drink only boiled water. In endemic countries, the most cost-effective strategy for reducing the incidence of typhoid fever is the institution of public health measures to ensure safe drinking water and sanitary disposal of excreta. The effects of these measures are long-term and reduce the incidence of other enteric infections, which are a major cause of morbidity and mortality in those areas.

Vaccines
In endemic areas, mass immunization with typhoid vaccines at regular intervals considerably reduces the incidence of infections. Routine typhoid vaccination is not recommended in the United States but is indicated for travelers to endemic areas, persons with intimate exposure to a documented S typhi carrier (eg, household contact), and microbiology laboratory personnel who frequently work with S typhi. Vaccines are not approved for use children younger than 2 years.

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Travelers should be vaccinated at least one week prior to departing for an endemic area. Because typhoid vaccines lose effectiveness after several years, consultation with a specialist in travel medicine is advised if the individual is traveling several years after vaccination. The only absolute contraindication to vaccination is a history of severe local or systemic reactions following a previous dose. The typhoid vaccines available in the United States have not been studied in pregnant women. Currently, the 3 typhoid fever vaccines include injected Vi capsular polysaccharide (ViCPS; Typhim Vi, Pasteur Merieux) antigen, enteric Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) live-attenuated vaccine, and an acetone-inactivated parenteral vaccine (used only in members of the armed forces). The efficacy of both vaccines available to the general public approaches 50%. o Vi capsular polysaccharide antigen vaccine is composed of purified Vi antigen, the capsular polysaccharide elaborated by S typhi isolated from blood cultures. Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 g IM) one week before travel. The vaccine manufacturer does not recommend the vaccine for children younger than 2 years. Booster doses are needed every 2 years to maintain protection if continued or renewed exposure is expected. Adverse effects include fever, headache, erythema, and/or induration of 1 cm or greater. In a study conducted in Nepal, the ViCPS vaccine produced fewer local and systemic reactions than the control (the 23-valent

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pneumococcal vaccine).[55] Among school children in South Africa, ViCPS produced less erythema and induration than the control (bivalent vaccine). A systemic review and meta-analysis of 5 randomized controlled trials on the efficacy and safety of ViCPS versus placebo or nontyphoid vaccine found a cumulative efficacy of 55% (95% CI, 30%-70%). The efficacy of vaccination with ViCPS has not been studied among persons from areas without endemic disease who travel to endemic regions or among children younger than 5 years. ViCPS has not been given to children younger than 1 year. Questions concerning Vi typhoid vaccine effectiveness in young children (ie, < 5 y) have inhibited its use in developing countries. Whether the vaccine is effective under programmatic conditions is also unclear. Sur et al conducted a phase IV effectiveness trial in slum-dwelling residents aged 2 years or older in India to determine vaccine protection. Participants (n=37,673) were randomly assigned to receive a single dose of either Vi vaccine or inactivated hepatitis A vaccine, according to geographic clusters. The mean rate of Vi vaccine coverage was 61% and 60% for the hepatitis A vaccine. Typhoid fever was diagnosed in 96 subjects in the hepatitis A vaccine group compared with 34 in the Vi vaccine group (no more than 1 episode was reported per individual). Protective effect for typhoid with the Vi vaccine was 61% (P < 0.001) compared with the hepatitis A vaccine group. Children vaccinated while aged 2-5 years had an 80% protection level. Unvaccinated members of the Vi vaccine clusters showed a protection level of 44%. The overall protection level with all Vi vaccine cluster residents was 57%. The authors concluded that the Vi vaccine was effective in young children and protected unvaccinated neighbors of Vi vaccinees.[56] Ty21a is an oral vaccine that contains live attenuated S typhi Ty21a strains in an enteric-coated capsule. The vaccine elicits both serum and intestinal antibodies and cell-mediated immune responses. In the United States, primary vaccination with Ty21a consists of one entericcoated capsule taken on alternate days to a total of 4 capsules. The capsules must be refrigerated (not frozen), and all 4 doses must be taken to achieve maximum efficacy. The optimal booster schedule has not been determined; however, the longest reported follow-up study of vaccine trial subjects indicated that efficacy continued for 5 years after vaccination. The manufacturer recommends revaccination with the entire 4-dose series every 5 years if continued or renewed exposure to S typhi is expected. This vaccine may be inactivated if given within 3 days of antibiotics. Adverse effects are rare. They include abdominal discomfort, nausea, vomiting, fever, headache, and rash or urticaria. The vaccine manufacturer of Ty21a recommends against use in children younger than 6 years. It should not be administered to immunocompromised persons; the parenteral vaccines present theoretically safer alternatives for this group. A systemic review and meta-analysis of 4 randomized controlled trials on the efficacy and safety of Ty21a versus placebo or nontyphoid vaccine found a cumulative efficacy of 51% (95% CI, 36%-62%). The efficacy of Ty21a has not been studied among persons from areas without endemic disease who travel to disease-endemic regions.

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Acetone-inactivated parenteral vaccine is currently available only to members of the US Armed Forces. Efficacy rates for this vaccine range from 75%-94%. Booster doses should be administered every 3 years if continued or renewed exposure is expected. o The parenteral heat-phenolinactivated vaccine (Wyeth-Ayerst) has been discontinued. o No information has been reported concerning the use of one vaccine as a booster after primary vaccination with a different vaccine. However, using either the series of 4 doses of Ty21a or 1 dose of ViCPS for persons previously vaccinated with parenteral vaccine is a reasonable alternative to administration of a booster dose of parenteral inactivated vaccine. o A more effective vaccine may be on the horizon. An investigational vaccine using ViCPS conjugated to the nontoxic recombinant pseudomonas exotoxin A (Vi-rEPA) has been studied in a randomized controlled trial. The vaccine was given to children aged 2-5 years and showed an efficacy of 89% (95% CI, 76%-97%) after 3.8 years. VirEPA has not been approved for use in the United States.

Complications

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Neuropsychiatric manifestations (In the past 2 decades, reports from disease-endemic areas have documented a wide spectrum of neuropsychiatric manifestations of typhoid fever.) o A toxic confusional state, characterized by disorientation, delirium, and restlessness, is characteristic of late-stage typhoid fever. In some cases, these and other neuropsychiatric features dominate the clinical picture at an early stage. o Facial twitching or convulsions may be the presenting feature. Meningismus is not uncommon, but frank meningitis is rare. Encephalomyelitis may develop, and the underlying pathology may be that of demyelinating leukoencephalopathy. In rare cases, transverse myelitis, polyneuropathy, or cranial mononeuropathy develops. o Stupor, obtundation, or coma indicates severe disease. o Focal intracranial infections are uncommon, but multiple brain abscesses have been reported.[57] o Other less-common neuropsychiatric manifestations events have included spastic paraplegia, peripheral or cranial neuritis, Guillain-Barr syndrome, schizophrenialike illness, mania, and depression. Respiratory o Cough o Ulceration of posterior pharynx o Occasional presentation as acute lobar pneumonia (pneumotyphoid) Cardiovascular o Nonspecific electrocardiographic changes occur in 10%-15% of patients with typhoid fever. o Toxic myocarditis occurs in 1%-5% of persons with typhoid fever and is a significant cause of death in endemic countries. Toxic myocarditis occurs in patients who are severely ill and toxemic and is characterized by tachycardia, weak pulse and heart sounds, hypotension, and electrocardiographic abnormalities. o Pericarditis is rare, but peripheral vascular collapse without other cardiac findings is increasingly described. Pulmonary manifestations have also been reported in patients with typhoid fever.[58] Hepatobiliary o Mild elevation of transaminases without symptoms is common in persons with typhoid fever.

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Prognosis

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The prognosis among persons with typhoid fever depends primarily on the speed of diagnosis and initiation of correct treatment. Generally, untreated typhoid fever carries a mortality rate of 10%-20%. In properly treated disease, the mortality rate is less than 1%.

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Jaundice may occur in persons with typhoid fever and may be due to hepatitis, cholangitis, cholecystitis, or hemolysis. o Pancreatitis and accompanying acute renal failure and hepatitis with hepatomegaly have been reported.[59] Intestinal manifestations o The 2 most common complications of typhoid fever include intestinal hemorrhage (12% in one British series) and perforation (3%-4.6% of hospitalized patients). o From 1884-1909 (ie, preantibiotic era), the mortality rate in patients with intestinal perforation due to typhoid fever was 66%-90% but is now significantly lower. Approximately 75% of patients have guarding, rebound tenderness, and rigidity, particularly in the right lower quadrant. o Diagnosis is particularly difficult in the approximately 25% of patients with perforation and peritonitis who do not have the classic physical findings. In many cases, the discovery of free intra-abdominal fluid is the only sign of perforation. Genitourinary manifestations o Approximately 25% of patients with typhoid fever excrete S typhi in their urine at some point during their illness. [60] o Immune complex glomerulitis and proteinuria have been reported, and IgM, C3 antigen, and S typhi antigen can be demonstrated in the glomerular capillary wall. o Nephritic syndrome may complicate chronic S typhi bacteremia associated with urinary schistosomiasis. o Nephrotic syndrome may occur transiently in patients with glucose-6-phosphate dehydrogenase deficiency. o Cystitis: Typhoid cystitis is very rare. Retention of urine in the typhoid state may facilitate infection with coliforms or other contaminants. Hematologic manifestations o Subclinical disseminated intravascular coagulation is common in persons with typhoid fever. [61] o Hemolytic-uremic syndrome is rare. o Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency. Musculoskeletal and joint manifestations o Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal wall and thigh muscles. [62] o Clinically evident polymyositis may occur. o Arthritis is very rare and most often affects the hip, knee, or ankle. Late sequelae (rare in untreated patients and exceedingly rare in treated patients) [63] o Neurologic - Polyneuritis, paranoid psychosis, or catatonia o Cardiovascular - Thrombophlebitis of lower-extremity veins o Genitourinary -Orchitis o Musculoskeletal Periostitis, often abscesses of the tibia and ribs Spinal abscess (typhoid spine; very rare)

An unspecified number of patients experience long-term or permanent complications, including neuropsychiatric symptoms and high rates of gastrointestinal cancers.

Patient Education

Because vigilant hand hygiene, vaccination, and the avoidance of risky foods and beverages are mainstays of prevention, educating travelers before they enter a disease-endemic region is important. Because the protection offered by vaccination is at best partial, close attention to personal, food, and water hygiene should be maintained. The US Centers for Disease Control and Prevention dictum to "boil it, cook it, peel it, or forget it" is a good rule in any circumstance. If disease occurs while abroad despite these precautions, one can usually call the US consulate for a list of recommended doctors. For excellent patient education resources, visit eMedicine's Public Health Center. Also, see eMedicine's patient education article Foreign Travel. Case study o A wealthy middle-aged man presented to his physician a few days after the onset of flulike symptoms, including fever, myalgias, chills, severe abdominal pain, and a cough, in addition to severe abdominal pain. Over the next 2 weeks, he lost a great deal of weight. He had intermittent but ever-increasing fevers. About 3 weeks after the onset of symptoms, he developed a few pale, salmon-colored macules on his trunk. His cough became much more frequent and severe. He became delirious, listlessly wandering around the house fiddling with doorknobs. During the fourth week of his illness, he rapidly declined with increasing somnolence. After nearly 4 weeks of illness, he died surrounded by his loving family. o The patient was Prince Albert, the Consort to Queen Victoria. He was diagnosed with typhoid fever. His personal physician, Sir William Jenner, a leading expert on the disease, diagnosed typhoid fever. Prince Albert received the best therapy of the day.

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