thyfoid fever

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Thyfoid Fever

Introduction

Background

Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illnesscaused primarily by Salmonella typhi. The protean manifestations of typhoid fever makethis disease a true diagnostic challenge. The classic presentation includes fever,malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a gruelingillness that may progress to delirium, obtundation, intestinal hemorrhage, bowelperforation, and death within one month of onset. Survivors may be left with long-term orpermanent neuropsychiatric complications.

S typhihas been a major human pathogen for thousands of years, thriving in conditionsof poor sanitation, crowding, and social chaos. It may have responsible for the GreatPlague of Athens at the end of the Pelopennesian War.1 The name S typhi is derivedfrom the ancient Greek typhos, an ethereal smoke or cloud that was believed to causedisease and madness. In the advanced stages of typhoid fever, the patient's level ofconsciousness is truly clouded. Although antibiotics have markedly reduced thefrequency of typhoid fever in the developed world, it remains endemic in developingcountries.2

Transmission

S typhihas 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% ofhealthy 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. Withtoll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognizepathogen-associated molecular patterns (PAMPs) such as flagella andlipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells andneutrophils with interleukin 8 (IL-8), causing inflammation and suppressing theinfection.5,6
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In contrast to the nontyphoidal salmonellae, S typhienters the host's system primarilythrough the distal ilium. S typhihas specialized fimbriae that adhere to the epitheliumover clusters of lymphoid tissue in the ilium (Peyer patches), the main relay point formacrophages traveling from the gut into the lymphatic system. S typhihas a Vi capsularantigen that masks PAMPs, avoiding neutrophil-based inflammation. The bacteria theninduce their host macrophages to attract more macrophages.5

It co-opts the macrophages' cellular machinery for their own reproduction7as it is carriedthrough the mesenteric lymph nodes to the thoracic duct and the lymphatics and thenthrough to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymphnodes. Once there, the S typhibacteria pause and continue to multiply until some criticaldensity is reached. Afterward, the bacteria induce macrophage apoptosis, breaking outinto the bloodstream to invade the rest of the body.6

The gallbladder is then infected via either bacteremia or direct extension of S typhiinfected bile. The result is that the organism re-enters the gastrointestinal tract in the bileand reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed inthe stool and are then available to infect other hosts.6,2


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Life cycle ofSalmonella typhi.

Risk factors

S typhiare able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptorantagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydriadecrease stomach acidity and facilitate S typhiinfection.6

HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonellainfection; however, the data and opinions in the literature as to whether this is true forStyphiinfection 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,PARK2and PACGRcode for a protein aggregate that is essential for breaking down the

bacterial signaling molecules that dampen the macrophage response. Polymorphisms intheir shared regulatory region are found disproportionately in persons infected withMycobacterium lepraeand S typhi.12

On the other hand, protective host mutations also exist. The fimbriae ofS typhibind invitro to cystic fibrosis transmembrane conductance receptor (CFTR), which is expressedon the gut membrane. Two to 5% of white persons are heterozygous for the CFTRmutation F508del, which is associated with a decreased susceptibility to typhoid fever,as well as to cholera and tuberculosis. The homozygous F508del mutation in CFTR isassociated with cystic fibrosis. Thus, typhoid fever may contribute to evolutionarypressure that maintains a steady occurrence of cystic fibrosis, just as malariamaintainssickle cell disease in Africa.13,14

Environmental and behavioral risk factors that are independently associated with typhoidfever include eating food from street vendors, living in the same household withsomeone who has new case of typhoid fever, washing the hands inadequately, sharingfood from the same plate, drinking unpurified water, and living in a household that doesnot have a toilet.15,12As the middle class in south Asia grows, some hospitals there areseeing a large number of typhoid fever cases among relatively well-off universitystudents who live in group households with poor hygeine.16American clinicians shouldkeep this in mind, as members of this cohort often come to the United States for higherdegrees.

Frequency

United States

Since 1900, improved sanitation and successful antibiotic treatment have steadilydecreased the incidence of typhoid fever in the United States. In 1920, 35,994 cases oftyphoid fever were reported. In 2006, there were 314.

Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had beenoutside of the country within the preceding 30 days. Two thirds of these individuals had
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just journeyed from the Indian subcontinent. The 3 known outbreaks of typhoid feverwithin the United States were traced to imported food or to a food handler from anendemic region. Remarkably, only 17% of cases acquired domestically were traced to acarrier.17

International

Typhoid fever occurs worldwide, primarily in developing nations whose sanitaryconditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, theCaribbean, and Oceania, but 80% of cases come from Bangladesh, China, India,Indonesia, Laos, Nepal, Pakistan, or Vietnam.18Within those countries, typhoid fever ismost common in underdeveloped areas. Typhoid fever infects roughly 21.6 millionpeople (incidence of 3.6 per 1,000 population) and kills an estimated 200,000 peopleevery year.19

In the United States, most cases of typhoid fever arise in international travelers. Theaverage yearly incidence of typhoid fever per million travelers from 1999-2006 by countyor 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

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.17Untreated typhoid fever is a life-threateningillness of several weeks' duration with long-term morbidity often involving the centralnervous system. The case fatality rate in the United States in the pre-antibiotic era was9%-13%.20

Race

Typhoid fever has no racial predilection.

Sex

Fifty-four percent of typhoid fever cases in the United States reported between 1999 and2006 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 behigher. The presentations in these age groups may be atypical, ranging from a mild


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febrile illness to severe convulsions, and the S typhiinfection may go unrecognized. Thismay account for conflicting reports in the literature that this group has either a very highor a very low rate of morbidity and mortality.16,21

Clinical

History

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

Classic typhoid fever syndrome

Typhoid fever begins 7-14 days after ingestion ofS typhi. The fever pattern is stepwise,characterized by a rising temperature over the course of each day that drops by thesubsequent morning. The peaks and troughs rise progressively over time.

Over the course of the first week of illness, the notorious gastrointestinal manifestationsof the disease develop. These include diffuse abdominal pain and tenderness and, insome cases, fierce colicky right upper quadrant pain. Monocytic infiltration inflamesPeyer patches and narrows the bowel lumen, causing constipation that lasts the durationof 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 (39-40C). 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 resolvewithin 2-5 days.2 These are bacterial emboli to the dermis and occasionally develop inpersons with shigellosis or nontyphoidal salmonellosis.22

During the second week of illness, the signs and symptoms listed above progress. Theabdomen becomes distended, and soft splenomegaly is common. Relative bradycardiaand 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 significantweight loss. The conjunctivae are infected, and the patient is tachypneic with a threadypulse and crackles over the lung bases. Abdominal distension is severe. Some patientsexperience foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual maydescend into the typhoid state, which is characterized by apathy, confusion, and evenpsychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. Thiscomplication 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 abdominaldistension slowly improve over a few days. Intestinal and neurologic complications maystill occur in surviving untreated individuals. Weight loss and debilitating weakness lastmonths. Some survivors become asymptomatic S typhicarriers and have the potential totransmit the bacteria indefinitely.16,23,24,2,6

Various presentations of typhoid fever
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Incubation Week 1 Week 2 Week 3 Week 4 Post

Systemic Recoveryphase ordeath(15% ofuntreatedcases)

10%-20%relapse;3%-4%chroniccarriers;long-termneurologicsequelae

(extremelyrare);gallbladdercancer(RR=167;carriers)

Stepladder feverpattern or insidiousonset fever

Verycommona

Very common

Acute high fever Very rareb

Chills Almost allc

Rigors Uncommon

Anorexia Almost all

Diaphoresis Very common

Neurologic

Malaise Almost all Almost all Typhoidstate(common)Insomnia Very

common

Confusion/delirium Commond Verycommon

Psychosis Very rare Common

Catatonia Very rare

Frontal headache(usually mild)

Verycommon

Meningeal signs Raree Rare

Parkinsonism Very rare

Ear, nose, and throat

Coated tongue Very

common

Sore throatf

Pulmonary

Mild cough Common

Bronchitic cough Common

Rales Common

Pneumonia Rare Rare Common


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The clinical course of a given individual with typhoid fever may deviate from the abovedescription of classic disease. The timing of the symptoms and host response may varybased on geographic region, race factors, and the infecting bacterial strain. Thestepladder fever pattern that was once the hallmark of typhoid fever now occurs in asfew as 12% of cases. In most contemporary presentations of typhoid fever, the fever hasa steady insidious onset.

Young children, individuals with AIDS, and one third of immunocompetent adults whodevelop typhoid fever develop diarrhea rather than constipation. In addition, in somelocalities, typhoid fever is generally more apt to cause diarrhea than constipation.

Atypical manifestations of typhoid fever include isolated severe headaches that maymimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe

jaundice, or fever alone. Some patients, especially in India and Africa, present primarilywith neurologic manifestations such as delirium or, in extremely rare cases, parkinsoniansymptoms or Guillain-Barr syndrome. Other unusual complications includepancreatitis,25meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body.2

Table 1. Incidence and Timing of Various Manifestations of Untreated TyphoidFever2,26,27,28,29,30

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

Treated typhoid fever

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

Physical

See History.

Causes

S typhiand Salmonella paratyphicause typhoid fever.

Differential Diagnoses

Abdominal Abscess MalariaAmebic Hepatic AbscessesRickettsial diseasesAppendicitis Toxoplasmosis
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Brucellosis TuberculosisDengue Fever TularemiaInfluenza TyphusLeishmaniasis

Other Problems to Be Considered

EndocarditisConnective-tissue diseaseLymphoproliferative disorders

Workup

Laboratory 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 The criterion standard for diagnosis of typhoid fever has long been culture

isolation of the organism. Cultures are widely considered 100% specific.o Culture of bone marrow aspirate is 90% sensitive until at least 5 days

after commencement of antibiotics. However, this technique is extremelypainful, which may outweigh its benefit.31

o Blood, intestinal secretions (vomitus or duodenal aspirate), and stool

culture results are positive for S typhi in approximately 85%-90% ofpatients with typhoid fever who present within the first week of onset.

They decline to 20%-30% later in the disease course. In particular, stoolculture may be positive for S typhi several days after ingestion of thebacteria secondary to inflammation of the intraluminal dendritic cells.Later in the illness, stool culture results are positive because of bacteriashed through the gallbladder.

o Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Large-volume

(10-30 mL) blood culture and clot culture may increase the likelihood ofdetection.32

o Stool culture alone yields a sensitivity of less than 50%, and urine culture

alone is even less sensitive. Cultures of punch-biopsy samples of rosespots reportedly yield a sensitivity of 63% and may show positive resultseven after administration of antibiotics. A single rectal swab culture upon

hospital admission can be expected to detect S typhi in 30%-40% ofpatients. S typhi has also been isolated from the cerebrospinal fluid,peritoneal fluid, mesenteric lymph nodes, resected intestine, pharynx,tonsils, abscess, and bone, among others.

o Bone marrow aspiration and blood are cultured in a selective medium (eg,

10% aqueous oxgall) or a nutritious medium (eg, tryptic soy broth) andare incubated at 37C for at least 7 days. Subcultures are made daily toone selective medium (eg, MacConkey agar) and one inhibitory medium(eg, Salmonella-Shigella agar). Identification of the organism with these
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conventional culture techniques usually takes 48-72 hours fromacquisition.

Table 2. Sensitivities of Cultures2,32,33,34

Open table in new window

[ CLOSE WINDOW ]

Table

Incubation Week 1 Week 2 Week 3 Week 4

Bone marrowaspirate (0.5-1 mL)

90% (may decrease after 5 d of antibiotics)

Blood (10-30 mL),stool, or duodenalaspirate culture

40%-80% ~20% Variable (20%-60%)

Urine 25%-30%, timing unpredictable

Incubation Week 1 Week 2 Week 3 Week 4

Bone marrowaspirate (0.5-1 mL)

90% (may decrease after 5 d of antibiotics)

Blood (10-30 mL),stool, or duodenalaspirate culture

40%-80% ~20% Variable (20%-60%)

Urine 25%-30%, timing unpredictable

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 ofPCR using two primers with different sequences within the H1-d flagellin gene ofS typhi, offers the best sensitivity and specificity. Combining assays of blood andurine, this technique has achieved a sensitivity of 82.7% and reported specificityof 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 withcultures 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 ofS typhi. Neither sensitive nor specific, the Widal test is no longer anacceptable clinical method.


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o Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect

enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M(IgM) and IgG antibodies to S typhi polysaccharide, as well asmonoclonal antibodies against S typhi flagellin,37 are promising, but thesuccess rates of these assays vary greatly in the literature.

Other nonspecific laboratory studies

o Most patients with typhoid fever are moderately anemic, have an elevatederythrocyte sedimentation rate (ESR), thrombocytopenia, and relativelymphopenia.

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 distinguishingtyphoid from viral hepatitis. A ratio of greater than 9:1 supports adiagnosis of acute viral hepatitis, while ratio of less than 9:1 supportstyphoid hepatitis.38

Imaging Studies

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 (seeLab 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 mostcommonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow butmay 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) necrosisof 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 largecollections 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
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and may show evidence of cholecystitis. Liver biopsy specimens from patients withtyphoid fever often show cloudy swelling, balloon degeneration with vacuolation ofhepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli canbe observed at these sites.2,6

Staging

The proper treatment approach to typhoid fever depends on whether the illness iscomplicated 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 severemanifestations. Depending on the adequacy of diagnosis and treatment, complicateddisease may develop in up to 10% of treated patients. Delirium, obtundation, stupor,coma, or shock demands a particularly aggressive approach

Treatment

Medical Care

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

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 foodfor 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 ofsafely.

Surgical Care

Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefersimple closure of the perforation with drainage of the peritoneum. Small-bowel resectionis indicated for patients with multiple perforations.

If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder shouldbe resected. Cholecystectomy is not always successful in eradicating the carrier statebecause of persisting hepatic infection.

Consultations

An infectious disease specialist should be consulted. Consultation with a surgeon isindicated upon suspected gastrointestinal perforation, serious gastrointestinalhemorrhage, cholecystitis, or extraintestinal complications (arteritis, endocarditis, organabscesses).
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Diet

Fluids and electrolytes should be monitored and replaced diligently. Oral nutrition with asoft 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 withmost systemic diseases, rest is helpful, but mobility should be maintained if tolerable.The patient should be encouraged to stay home from work until recovery.

Medication

Antibiotics

Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. As ageneral principle of antimicrobial treatment, intermediate susceptibility should be

regarded as equivalent to resistance. Between 1999 and 2006, 13% ofS typhi isolatescollected in the United States were multidrug resistant.

Until susceptibilities are determined, antibiotics should be empiric, for which there arevarious recommendations. The authors of this article consider the 2003 World HealthOrganization (WHO) guidelines to be outdated. These recommend fluoroquinolonetreatment for both complicated and uncomplicated cases of typhoid fever, but 38% ofStyphiisolates taken in the United States in 2006 were fluoroquinolone resistant (nalidixicacidresistant S typhi [NARST]), and the rate of multidrug resistance was 13%.(Multidrug-resistant S typhi 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 themajor basis of empiric antibiotic choice. It may soon become necessary to treat all casespresumptively for multidrug resistance until sensitivities are obtained.

Note that nalidixic acid is a nontherapeutic drug that is used outside of the United Statesas a stand-in for fluoroquinolones in sensitivity assays. In the United States, it is stillused specifically forS typhiinfection.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 Styphi and S paratyphi strains (multidrug resistant [MDR] S typhi or S paratyphi)developed simultaneous plasmid-mediated resistance to all three of these agents.

Fluoroquinolones are now recommended by most authorities for the treatment of typhoidfever. They are highly effective against susceptible organisms, yielding a better cure ratethan cephalosporins. Unfortunately, resistance to first-generation fluoroquinolones iswidespread in many parts of Asia.


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In recent years, third-generation cephalosporins have been used in regions with highfluoroquinolone resistance rates, particularly in south Asia and Vietnam. Unfortunately,sporadic resistance has been reported, so it is expected that these will become lessuseful over time.39

Mechanisms of antibiotic resistance

The genes for antibiotic resistance in S typhi and S paratyphi are acquired fromEscherichia coli and other gram-negative bacteria via plasmids. The plasmids containcassettes of resistance genes that are incorporated into a region of the Salmonellagenome called an integron. Some plasmids carry multiple cassettes and immediatelyconfer resistance to multiple classes of antibiotics. This explains the sudden appearanceof MDR strains ofS typhiand S paratyphi, often without intermediate strains that haveless-extensive resistance.

The initial strains of antibiotic-resistant S typhiand S paratyphicarried chloramphenicolacetyltransferase type I, which encodes an enzyme that inactivates chloramphenicol viaacetylation. MDR strains may carry dihydrofolate reductase type VII, which confersresistance to trimethoprim. Interestingly, in areas where these drugs have fallen out ofuse, S typhi has reverted to wild type, and they are often more effective than neweragents.40,41,42,30

Resistance to fluoroquinolones is evolving in an ominous direction. Fluoroquinolonestarget DNA gyrase and topoisomerase IV, bacterial enzymes that are part of a complexthat uncoils and recoils bacterial DNA for transcription.43 S typhi most commonlydevelops fluoroquinolone resistance through specific mutations in gyrA andparC, whichcode for the binding region of DNA gyrase and topoisomerase IV, respectively.

A single point mutation gyrA confers partial resistance. If a second gyrA point mutation isadded, the resistance increases somewhat. However, a mutation in parCadded to asingle 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 bacterialclearance is higher in both partially and fully resistant strains than in fully susceptiblestrains.18

The third-generation fluoroquinolone gatifloxacin appears to be highly effective againstall known clinical strains of S typhi both in vitro and in vivo. However, any two of anumber of gyrA mutations, when added to the parC mutation, confer full in vitroresistance. Although such a combination has yet to be discovered in vivo, all of thesemutations exist in clinic strains, and it seems highly likely that a gatifloxacin-resistant

strain will be encountered clinically if selective pressure with fluoroquinolones continuesto 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.
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Nearly half ofS typhiisolates found in the United States now come from travelers to theIndian subcontinent, where fluoroquinolone resistance is endemic (see Table 3). Therate of fluoroquinolone resistance in south and Southeast Asia and, to some extent, inEast 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 strainsremain predominant, and some acquired resistance to fluoroquinolones by the early

2000s.

The most recent professional guideline for the treatment of typhoid fever in south Asiawas issued by the Indian Association of Pediatrics (IAP) in October 2006. Althoughthese guidelines were published for pediatric typhoid fever, the authors feel that they arealso applicable to adult cases. For empiric treatment of uncomplicated typhoid fever, theIAP recommends cefixime and, as a second-line agent, azithromycin. For complicatedtyphoid fever, they recommend ceftriaxone. Aztreonam and imipenem are second-lineagents for complicated cases.45The authors believe that the IAP recommendations havemore validity than the WHO recommendations for empiric treatments of typhoid fever inboth adults and children.

In high-prevalence areas outside the areas discussed above, the rate of intermediatesensitivity 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, forstrains that originate outside of south or Southeast Asia, the WHO recommendationsmay still be validthat uncomplicated disease should be treated empirically with oralciprofloxacin and complicated typhoid fever from these regions should be treated withintravenous ciprofloxacin.39,42,46,19,47

Antibiotic resistance is a moving target. Reports are quickly outdated, and surveys ofresistance may have limited geographic scope. Therefore, any recommendationregarding antibiotic treatment must be taken with a grain of salt. In the authors' opinion, ifthe origin of the infection is unknown, the combination of a first-generation

fluoroquinolone and a third-generation cephalosporin should be used.

Table 3. Antibiotic Recommendations by Origin and Severity

Open table in new window

[ CLOSE WINDOW ]

Table

Location Severity First-Line Antibiotics Second-Line Antibiotics

South Asia, East Asia 4548, 40

Uncomplicated Cefixime PO Azithromycin PO

Complicated Ceftriaxone IV orCefotaxime IV

Aztreonam IV orImipenem IV
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*Note that the combination of azithromycin and fluoroquinolones is not recommendedbecause it may cause QT prolongation and is relatively contraindicated.

Future directions

Researchers in Cameroon report that a compound derived from the seeds ofTurraeanthus africanus, an African folk remedy for typhoid fever, is active against Styphi in vitro.51 Perhaps they are on their way to creating an addition to the shrinkingarsenal of effective antimicrobials.

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibitingprotein synthesis. Effective against gram-negative and gram-positive bacteria. Since itsintroduction 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 appearand 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 in3-5 d. Reduced preantibiotic-era case-fatality rates from 10%-15% to 1%-4%. Curesapproximately 90% of patients. Administered PO unless patient is nauseous orexperiencing diarrhea; in such cases, IV route should be used initially. IM route shouldbe avoided because it may result in unsatisfactory blood levels, delaying defervescence.

Dosing

Interactions

Contraindications Precautions

Adult

500 mg PO/IV q4h until defervescence, then q6h for a total course of 14 d

Pediatric

50-75 mg/kg/d PO/IV divided q6h

Dosing

Interactions Contraindications

Precautions

Concurrently with barbiturates, chloramphenicol serum levels may decrease whilebarbiturate levels may increase, causing toxicity; manifestations of hypoglycemia mayoccur with sulfonylureas; rifampin may reduce serum levels, presumably through hepaticenzyme induction; may increase effects of anticoagulants; may increase serum


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Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies inanimals

Precautions

Adjust dose in renal impairment; may enhance chance of candidiasis

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

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

Dosing

Interactions

Contraindications

Precautions

Adult

6.5-10 mg/kg/d PO bid/tid; can be given IV if necessary; 160 mg TMP/800 mg SMZ POq12h for 10-14 d

Pediatric

2 months: 15-20 mg/kg/d PO, based on TMP, tid/qid for 14 d

Dosing

Interactions

Contraindications

Precautions

May increase PT when used with warfarin (perform coagulation tests and adjust doseaccordingly); coadministration with dapsone may increase blood levels of both drugs;

coadministration of diuretics increases incidence of thrombocytopenia purpura in elderlypersons; phenytoin levels may increase with coadministration; may potentiate effects ofmethotrexate in bone marrow depression; hypoglycemic response to sulfonylureas mayincrease with coadministration; may increase levels of zidovudine

Dosing

Interactions

Contraindications

Precautions


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Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;may use if benefits outweigh risk to fetus

Precautions

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCcounts frequently; discontinue therapy if significant hematologic changes occur; goiter,diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or highdoses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin);caution in folate deficiency (eg, patients with long-term alcoholism, elderly persons,those receiving anticonvulsant therapy, or those with malabsorption syndrome);hemolysis may occur in patients with G-6-PD deficiency; patients with AIDS may nottolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform

urinalyses and renal function tests during therapy); administer fluids to preventcrystalluria and stone formation

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA,Staphylococcus epidermidis, and most gram-negative organisms but no activity againstanaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Continuetreatment 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 strainsand have intracellular antibacterial activity.Not currently recommended for use in children and pregnant women because ofobserved potential for causing cartilage damage in growing animals. However,arthropathy has not been reported in children following use of nalidixic acid (an earlierquinolone known to produce similar joint damage in young animals) or in children withcystic fibrosis, despite high-dose treatment.

Adult

20-30 mg/kg/d PO bid for 14 d, but shorter courses may be adequate; 250-500 mg PObid for 7-14 d

Pediatric

18 years: Administer as in adults


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Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h

before or after taking fluoroquinolones; cimetidine may interfere with metabolism of

fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increaseserum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and

digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy


Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal,hepatic, hematopoietic); adjust dose in renal function impairment; superinfections mayoccur with prolonged or repeated antibiotic therapy

Cefotaxime (Claforan)

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

Adult

2 g IV q6h

Pediatric

200 mg/kg/d IV in divided doses for 14 dInfants and children: 50-180 mg/kg/d IV/IM divided q4-6h>12 years: Administer as in adults

Probenecid may increase levels; coadministration with furosemide and aminoglycosidesmay increase nephrotoxicity

Pregnancy


Precautions

Adjust dose in severe renal impairment; associated with severe colitis


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1-2 g IV q12h

Pediatric

>7 days: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/dInfants and children: 50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d

Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, andaminoglycosides may increase nephrotoxicity

Pregnancy


Precautions

Adjust dose in renal impairment; caution predelivery and in breastfeeding; pseudobiliarylithiasis; non Clostridium difficile diarrhea

Cefoperazone (Cefobid)

Discontinued in the United States. Third-generation cephalosporin with gram-negativespectrum. Lower efficacy against gram-positive organisms.

Dosing

Interactions


Adult

2-4 g/d IV/IM divided bid; not to exceed 12 g/d

Pediatric

Not established; 100-150 mg/kg/d IV/IM divided q8-12h; not to exceed 12 g/d(suggested)

Dosing

Interactions

Contraindications

Precautions

Probenecid may increase levels; coadministration with furosemide and aminoglycosidesmay increase nephrotoxicity


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Pregnancy


Precautions

Adjust dose in severe renal impairment; has been associated with severe colitis

Ofloxacin (Floxin)

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

Dosing

Interactions


Adult

200-400 mg PO q12h

Pediatric


Dosing

Interactions

Contraindications

Precautions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 hbefore or after taking fluoroquinolones; cimetidine may interfere with metabolism offluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increaseserum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, anddigoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy


Precautions


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Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrug-resistant gram-negativeorganisms.

Dosing

Interactions

Contraindications

Precautions

Adult

500 mg PO qd for 7-14 d

Pediatric


Dosing

Interactions

Contraindications

Precautions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 hbefore or after taking fluoroquinolones; cimetidine may interfere with metabolism offluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increaseserum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, anddigoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy


Precautions


Corticosteroids


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Dexamethasone may decrease the likelihood of mortality in severe typhoid fever casescomplicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis hasbeen definitively ruled out by cerebrospinal fluid studies. To date, the most systematictrial of this has been a randomized controlled study in patients aged 3-56 years withsevere typhoid fever who were receiving chloramphenicol therapy. This study comparedoutcomes 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 every6 hours for 8 doses. The fatality rate in the dexamethasone arm was 10% versus 55.6%in the placebo arm (P =.003). Nonetheless, this point is still debated. A 2003 WHOstatement endorsed the use of steroids as described above, but reviews by eminentauthors in the New England Journal of Medicine (2002)6and the British Medical Journal(2006)53 do not refer to steroids at all. A 1991 trial compared patients treated with 12doses of dexamethasone 400 mg or 100 mg to a retrospective cohort in whom steroidswere 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 thatdexamethasone should be used in cases of severe typhoid fever.

Dexamethasone (Decadron)

Prompt administration of high-dose dexamethasone reduces mortality in patients withsevere typhoid fever without increasing incidence of complications, carrier states, orrelapse among survivors.

Dosing

Interactions

Contraindications

Precautions

Adult

3 mg/kg PO/IM/IV initially, followed by 8 doses of 1 mg/kg q6h

Pediatric

Not established

Follow-up

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 typhoidfever should finish their course intravenously and should remain in the hospital ifunable 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


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basis unless the patient is a public health risk or cannot be fully monitoredoutside the home.

Further Outpatient Care

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 weekafter therapy is discontinued, but relapse after 70 days has been reported. Inthese cases, the blood culture results are again positive, and high serum levelsof 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 newquinolone 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 geneticpredispositions 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. Depending on the antibiotic used, between 0% and 5.9% of treated patients

become chronic carriers. In some cases, the organism evades antibiotics bysequestering itself within gallstones orSchistosoma haematobium organismsthat 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 urinarycultures 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, theyshould 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 safedrinking water and sanitary disposal of excreta. The effects of these measuresare 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 intervalsconsiderably reduces the incidence of infections. Routine typhoid vaccination is notrecommended in the United States but is indicated for travelers to endemic areas,persons with intimate exposure to a documented S typhicarrier (eg, household contact),
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and microbiology laboratory personnel who frequently work with S typhi. Vaccines arenot approved for use children younger than 2 years.

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 inthe 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, andan acetone-inactivated parenteral vaccine (used only in members of the armedforces). The efficacy of both vaccines available to the general public approaches50%.

o Vi capsular polysaccharide antigen vaccine is composed of purified Vi

antigen, the capsular polysaccharide elaborated by S typhi isolated fromblood cultures.

Primary vaccination with ViCPS consists of a single parenteraldose of 0.5 mL (25 g IM) one week before travel. The vaccinemanufacturer does not recommend the vaccine for childrenyounger than 2 years. Booster doses are needed every 2 years tomaintain protection if continued or renewed exposure is expected.

Adverse effects include fever, headache, erythema, and/orinduration of 1 cm or greater. In a study conducted in Nepal, theViCPS vaccine produced fewer local and systemic reactions thanthe control (the 23-valent pneumococcal vaccine).55Among schoolchildren in South Africa, ViCPS produced less erythema andinduration than the control (bivalent vaccine).

A systemic review and meta-analysis of 5 randomized controlledtrials on the efficacy and safety of ViCPS versus placebo ornontyphoid vaccine found a cumulative efficacy of 55% (95% CI,30%-70%).

The efficacy of vaccination with ViCPS has not been studiedamong persons from areas without endemic disease who travel toendemic regions or among children younger than 5 years. ViCPShas not been given to children younger than 1 year.

Questions concerning Vi typhoid vaccine effectiveness in youngchildren (ie,


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than 1 episode was reported per individual). Protective effect fortyphoid with the Vi vaccine was 61% (P


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Complications

Neuropsychiatric manifestations (In the past 2 decades, reports from disease-

endemic areas have documented a wide spectrum of neuropsychiatricmanifestations 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 anearly stage.

o Facial twitching or convulsions may be the presenting feature. Meningismus

is not uncommon, but frank meningitis is rare. Encephalomyelitis maydevelop, and the underlying pathology may be that of demyelinatingleukoencephalopathy. In rare cases, transverse myelitis, polyneuropathy, orcranial 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 bytachycardia, weak pulse and heart sounds, hypotension, andelectrocardiographic abnormalities.

o Pericarditis is rare, but peripheral vascular collapse without other cardiac

findings is increasingly described. Pulmonary manifestations have alsobeen reported in patients with typhoid fever.58

Hepatobiliary

o Mild elevation of transaminases without symptoms is common in persons

with typhoid fever.o 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% ofhospitalized 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 nowsignificantly lower. Approximately 75% of patients have guarding,rebound tenderness, and rigidity, particularly in the right lower quadrant.
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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 signof perforation.

Genitourinary manifestations

o Approximately 25% of patients with typhoid fever excrete S typhi in their

urine at some point during their illness.o Immune complex glomerulitis60 and proteinuria have been reported, and

IgM, C3 antigen, and S typhi antigen can be demonstrated in theglomerular 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.o Hemolytic-uremic syndrome is rare.61

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.o Clinically evident polymyositis may occur.62

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)

o Neurologic - Polyneuritis, paranoid psychosis, orcatatonia63

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)

Prognosis

The prognosis among persons with typhoid fever depends primarily on the speed

of diagnosis and initiation of correct treatment. Generally, untreated typhoid fevercarries a mortality rate of 10%-20%. In properly treated disease, the mortality

rate is less than 1%. An unspecified number of patients experience long-term or permanent

complications, including neuropsychiatric symptoms and high rates ofgastrointestinal cancers.

Patient Education
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Because vigilant hand hygiene, vaccination, and the avoidance of risky foods and

beverages are mainstays of prevention, educating travelers before they enter adisease-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 forDisease 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 theseprecautions, one can usually call the US consulate for a list of recommendeddoctors.

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, severeabdominal pain, and a cough, in addition to severe abdominal pain. Overthe next 2 weeks, he lost a great deal of weight. He had intermittent butever-increasing fevers. About 3 weeks after the onset of symptoms, hedeveloped a few pale, salmon-colored macules on his trunk. His cough

became much more frequent and severe. He became delirious, listlesslywandering around the house fiddling with doorknobs. During the fourthweek of his illness, he rapidly declined with increasing somnolence. Afternearly 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 Albertreceived the best therapy of the day.

For the most up-to-date information, visit the Centers for Disease Control and

Prevention Travelers' Health Typhoid resource (www.cdc.gov/travel) or call theTravelers' Health automated information line at 877-FYI-TRIP. The World HealthOrganizations site (www.who.int/ith), International Society of Travel Medicinesite (www.istm.org), and Travel Doctor (www.traveldoctor.co.uk/diseases.htm )contain useful information as well, though the authors disagree with some of theWHOs antibiotic guidelines.

Miscellaneous

Special Concerns

Culture-confirmed typhoid fever (enteric fever) should be reported to the state healthdepartment.
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