TYPHOID FEVER

Salmonella organisms are responsible for a broad spectrum of clinical syndromes that include asymptomatic carriage, self-limited gastroenteritis, bacteremia, enteric fever, and metastatic focal infections. Some Salmonella serotypes, including Salmonella typhi and Salmonella paratyphi, are adapted to humans and have no other known natural hosts, whereas most other serotypes infect a variety of animals. Salmonella infections occur worldwide. Acute enteritis, the most frequent presentation, is usually self-limited, although bacteremia and focal extraintestinal infections may develop, especially in immunocompromised patients. The latter group has become more important and complex because of the increasing number of children who are compromised by A !S, organ transplantation, or chemotherapy. Enteric fever, or typhoid fever, is a severe systemic disease that is classically caused by Salmonella ser. Typhi "Salmonella typhi# and is found mainly in developing countries, but it is encountered worldwide because of international travel. $olecular technology has enabled classification at the gene level. !%A analysis has proved that all Salmonella organisms are closely related genetically as a single species with six subgroups& most isolates causing human or animal disease belong to subgroup '. The medical slang usage that treated each of the nearly (,)** serotypes as though it were a separate species has fallen out of favor. The preferred designation currently is the abbreviated version of the formal name by the +enters for !isease +ontrol and ,revention "+!+# "Table '#.
TABLE 1 -- Salmonella Nomenc !t"re Tr!dition! #$!%e S. typhi S. dublin S. typhimurium S. choleraesuis S. marina Form! N!me S. enterica - subsp. enterica ser. Typhi S. enterica subsp. enterica ser. !ublin S. enterica subsp. enterica ser. Typhimurium S. enterica subsp. enterica ser. +holeraesuis S. enterica subsp. houtenae ser. $arina &D& De$i%n!tion S. ser. Typhi S. ser. !ublin S. ser. Typhimurium S. ser. +holeraesuis S. ser. $arina

+!+, +enters for !isease +ontrol and ,revention& subsp, subspecies& ser., serotype.
*Some authorities prefer choleraesuis or enteritidis rather than enterica to describe the species.

ETIOLO'Y
.nteric fever, or typhoid fever, is caused by S. ser Typhi, S. ser. ,aratyphi A, S. ser. ,aratyphi / "Schottmuelleri#, and S. ser. ,aratyphi + "0irschfeldii#. 1arely, other Salmonella serotypes can cause a similar prolonged febrile illness. Salmonellae are gram-negative bacilli that belong to the .nterobacteriaceae family. They are non-spore-forming, nonencapsulated, and motile owing to peritrichous flagella. $ost strains ferment glucose, mannose, and mannitol to produce acid and gas "except S. typhi# but only rarely ferment lactose or sucrose. Salmonella organisms grow aerobically and are capable of facultative anaerobic growth. They are resistant to many physical agents but can be killed by heating to '2*34 ")5.53+# for 'hr or '5*34 "6*3+# for ') min. They remain viable at ambient or reduced temperatures for days and may survive for weeks in sewage, dried foodstuffs, pharmaceutical agents, and fecal material.

The following three kinds of surface antigens determine the reaction of Salmonella to specific antisera7 8 "somatic#, 0 "flagellar#, and 9i "capsular#. The O !nti%en$ are the heat-stable lipopolysaccharide components of the outer membrane& the H !nti%en$ are heat-labile proteins that can be present in phase ' or (. The :auffmann-;hite scheme commonly used to classify salmonellae serotypes is based on 8 and 0 antigens. Serotyping is important clinically because certain serotypes tend to be associated with specific clinical syndromes and because detection of an unusual serotype is sometimes useful in recogni<ing a commonsource outbreak. A virulence capsular polysaccharide "9i#, present on S. ser. Typhi, is also found on strains of S. ser. !ublin and S. ser. ,aratyphi + (S. ser. 0irschfeldii#.

EPIDE(IOLO'Y
The incidence, mode of transmission, and consequences of enteric fever differ significantly in developed and developing countries. The incidence has decreased markedly in developed countries. n the =nited States, about 5** cases of typhoid fever are reported each year, giving an annual incidence of less than *.( cases>'**,*** population, which is similar to that in ;estern .urope and ?apan. n Southern .urope, the annual incidence is 5.2@'5.) cases>'**,*** population. n developing countries, S. ser. Typhi is often the most common Salmonella isolate, with an incidence that can reach )** cases> '**,*** population "*.)A# and a high mortality rate. The ;orld 0ealth 8rgani<ation has estimated that at least '(.) million cases occur annually worldwide. /ecause humans are the only natural reservoir of S. ser. Typhi, direct or indirect contact with an infected person "sick or chronic carrier# is necessary for infection. ngestion of foods or water contaminated with human feces is the most common mode of transmission. ;aterborne outbreaks due to poor sanitation and direct fecal-oral spread due to poor personal hygiene are encountered, mainly in developing countries. 8ysters and other shellfish cultivated in water contaminated by sewage are also a source of widespread infection. n the =nited States about 6)A of the cases result from international travel. Travel to Asia "especially to ndia# and +entral or South America "especially $exico# is usually implicated. !omestically acquired enteric fever is most frequent in the southern and western =nited States and is usually caused by consumption of foods contaminated by individuals who are chronic carriers. +ongenital transmission of enteric fever can occur by transplacental infection from a bacteremic mother to her fetus. ntrapartum transmission is also possible, occurring by a fecal-oral route from a carrier mother.

PATHO'ENE)I)
The pathogenesis of Salmonella infections involves four complex processes that follow ingestion of the organism "4igure '#& they are "'# adherence to and invasion of $ cells in ,eyer patches, "(# survival and multiplication of bacteria in the macrophages of ,eyer patches, mesenteric lymph nodes, and extraintestinal organs of the reticuloendothelial system, "2# survival of bacteria in the blood stream, and "5# production of heat-labile, choleralike enterotoxin that increases cyclic adenosine monophosphate "cA$,# levels within intestinal crypts and causes a net efflux of electrolytes and water into the intestinal lumen. Several virulence factors seem to be important. $ore than a do<en specific genes encode virulence factors necessary for each step. Some virulence genes are shared by all salmonellae, and others are restricted to serotype. The variability of pathogenicity among Salmonella strains is related to the variable presence and expression of these virulence genes. nvasion of ,eyer patches is encoded by genes closely related to the invasion genes of Shigella and enteroinvasive E. coli. 0owever, S. ser. Typhi possesses a number of additional genes not found in Shigella that are responsible for the features of typhoid fever. The surface 9i capsular antigen found in S. ser. Typhi interferes with phagocytosis by preventing the binding of +2 to the surface of the bacterium. The ability of organisms to survive within macrophages after phagocytosis is an important virulence trait encoded by the phoP regulon& it may be related to metabolic effects on host cells. +irculating endotoxin, a lipopolysaccharide component of the bacterial cell wall, is thought to cause the prolonged

fever and toxic symptoms of enteric fever, although its levels in symptomatic patients are low. Alternatively, endotoxin-induced cytokine production by human macrophages may cause the systemic symptoms. The occasional occurrence of diarrhea may be explained by presence of a toxin related to cholera toxin and E. coli heat-labile enterotoxin.

Fi%+ 1 Selected events in Salmonella pathogenesis and associated virulence genes $ultiple factors predispose to Salmonella infection "Table (#. The dose of organisms ingested is an important determinant of the incubation period, symptoms, and severity of acute salmonellosis. Adult volunteer studies have shown that as inoculum si<e is increased, the incubation period decreases and severity increases. B5C Dastric acidity is an important barrier to infection. Achlorhydria, antacids, and rapid gastric emptying "after gastrectomy and gastroenterostomy# favor survival of ingested organisms. The hypochlorhydria and rapid gastric emptying time of neonates and young infants explain, at least in part, their vulnerability to symptomatic salmonellosis.
TABLE * -- F!ctor$ Predi$po$in% to SalmonellaInfection or Di$$emin!tion )ite of Defect Dastric acid barrier (ech!ni$m !nd & inic! )ettin% Achlorhydria Anatomic7 gastrectomy, gastroenterostomy 4unctional7 ingestion of buffers, vagotomy 1apid emptying "neonates, postgastrectomy# nflammatory bowel disease Tissue ischemia>infarction "sickle cell anemia, trauma# ,rior antibiotic therapy "results in increased infection and prolonged carriage# Sickle cell anemia "defect in alternate complement pathway# +hronic granulomatous disease

ntestinal mucosal barrier Dut flora 8psonins %eutrophils

TABLE * -- F!ctor$ Predi$po$in% to SalmonellaInfection or Di$$emin!tion )ite of Defect +ell-mediated immunity (ech!ni$m !nd & inic! )ettin% After organ transplantation or with defects associated with acquired immunodeficiency syndrome, infancy, malnutrition, or corticosteroid therapy !efects in type ' helper T-lymphocyte "Th'# functions "interleukin-'(>interferongamma axis#, including mutations in the genes for interleukin-'(1E' and interleukin-'( Sequestered organisms Schistosomiasis 1eticuloendothelial cells "typhoid fever# Solid tumors Dallbladder disease 1eticuloendothelial system 8verload with hemoglobin or iron "hemolytic anemia, such as sickle cell disease, thalassemia, bartonellosis, malaria# or impaired function due to malignancy, such as leukemia or lymphoma

Fi%+* ,athogenesis of Typhoid 4ever The inoculum si<e required to cause enteric fever in volunteers is '* ) @'*F S. ser. Typhi organisms. These estimates may be higher than in naturally acquired infection because the volunteers ingested the organisms in milk& stomach acidity is an important determinant of susceptibility to Salmonella. The bacteria invade through the ,eyer patches. 8rganisms are

transported to intestinal lymph nodes, where multiplication takes place within the mononuclear cells. $onocytes, unable to destroy the bacilli early in the disease process, carry these organisms into the mesenteric lymph nodes. 8rganisms then reach the bloodstream through the thoracic duct, causing a transient bacteremia. +irculating organisms reach the reticuloendothelial cells in the liver, spleen, and bone marrow and may seed other organs. After proliferation in the reticuloendothelial system, bacteremia recurs. The gallbladder is particularly susceptible to being infected. Gocal multiplication in the walls of the gallbladder produces large numbers of salmonellae, which reach the intestine through the bile "4igure (#. n younger children, the morphologic changes of S. ser. Typhi infection are less prominent than in older children and adults. 0yperplasia of ,eyer patches with necrosis and sloughing of overlying epithelium produces ulcers that may bleed. The mucosa and lymphatic tissue of the intestinal tract are severely inflamed and necrotic. =lcers heal without scarring. Strictures and intestinal obstruction virtually never occur after typhoid fever. The inflammatory lesion may occasionally penetrate the muscularis and serosa of the intestine and produce perforation. The mesenteric lymph nodes, liver, and spleen are hyperemic and generally reveal areas of focal necrosis. 0yperplasia of reticuloendothelial tissue with proliferation of mononuclear cells is the predominant finding. A mononuclear response may be seen in the bone marrow in association with areas of focal necrosis. nflammation of the gallbladder is focal, inconstant, and modest in proportion to the extent of local bacterial multiplication. /ronchitis is common. nflammation also may be observed in the form of locali<ed abscesses, pneumonia, septic arthritis, osteomyelitis, pyelonephritis, endophthalmitis, and meningitis. +ell-mediated immunity is important in protecting the human host against typhoid fever. !ecreased numbers of T lymphocytes are found in patients who are critically ill with typhoid fever. +arriers show impaired cellular reactivity to S. ser. Typhi antigens in the leukocyte migration inhibition test. n carriers, a large number of virulent bacilli pass into the intestine daily and are excreted in the stool, without entering the epithelium of the host.

&LINI&AL (ANIFE)TATION)
The incubation period is usually H@'5 days, but it may range from 2@2* days, depending mainly on the si<e of the ingested inoculum. The clinical manifestations of enteric fever depend on age. !uring the first week of illness, there is a stepwise, insidious increase in fever, which eventually becomes unremitting and is associated with systemic symptoms such as headache, lethargy, malaise, myalgia, and abdominal pain. n the second week, hepatosplenomegaly and rose spots can be found& headache is replaced by stupor. 1elative bradycardia is common in adults but not children. B25C !uring the third to fourth week of fever, intestinal hemorrhage and perforation are common& fever begins to show morning remissions, and there is a gradual decline in fever spikes. B2)C $yocarditis, shock, meningitis, and pneumonia can complicate the course. !iarrhea with blood and fecal leukocytes is commonly present in children during the first several weeks of illness, although in a few patients it does not begin until the third week. 8ccasionally, resolution does not occur until 6 weeks after onset. .ven in the preantibiotic era, recurrences sometimes were seen after apparent resolution of enteric fever. !eath related to central nervous system involvement, intestinal hemorrhage, or perforation generally does not occur until after the first week of illness. B26C n infants and young children, S. typhi can manifest less impressive fever and toxicity, causing a nonspecific syndrome that may be misinterpreted as a viral infection.B2HC B2IC )&HOOL,A'ED &HILDREN AND ADOLE)&ENT) The onset of symptoms is insidious. nitial symptoms of fever, malaise, anorexia, myalgia, headache, and abdominal pain develop over (@2 days. Although diarrhea having a pea soup

consistency may be present during the early course of the disease, constipation later becomes a more prominent symptom. +ough and epistaxis may ensue. Severe lethargy may develop in some children. Temperature, which increases in a stepwise fashion, becomes an unremitting and high fever within ' wk, often reaching 5*3+. !uring the (nd week of illness, high fever is sustained, and fatigue, anorexia, cough, and abdominal symptoms increase in severity. ,atients appear acutely ill, disoriented, and lethargic. !elirium and stupor may be observed. ,hysical findings include a relative bradycardia, which is disproportionate to the high fever. 0epatomegaly, splenomegaly, and distended abdomen with diffuse tenderness are very common. n about )*A of patients with enteric fever, a macular or maculopapular rash " ro$e $pot$# appears on about the Hth@'*th day. Gesions are usually discrete, erythematous, and '@) mm in diameter& the lesions are slightly raised and blanch on pressure. They appear in crops of '*@') lesions on the lower chest and abdomen and last (@2 days. They leave a slight brownish discoloration of the skin on healing. +ultures of the lesions have a 6*A yield for Salmonella organisms. 1honchi and scattered rales may be heard on auscultation of the chest. %ausea and vomiting if occurring in the (nd or 2rd week suggest a complication. f no complications occur, the symptoms and physical findings gradually resolve within (@5 wk, but malaise and lethargy may persist for an additional '@( mo. ,atients may be emaciated by the end of the illness. .nteric fever caused by nontyphoidal Salmonella is usually milder, with a shorter duration of fever and a lower rate of complications. INFANT) AND YO#N' &HILDREN -./YR0 .nteric fever is relatively rare in this age group in endemic areas. Although clinical sepsis can occur, the disease is surprisingly mild at presentation, making the diagnosis difficult. $ild fever and malaise, misinterpreted as a viral syndrome, occur in infants with culture-proven typhoid fever. !iarrhea is more common in young children with typhoid fever than in adults, leading to a diagnosis of acute gastroenteritis. NEONATE) n addition to its ability to cause abortion and premature delivery, enteric fever during late pregnancy may be transmitted vertically. The neonatal disease usually begins within 2 days of delivery. 9omiting, diarrhea, and abdominal distention are common. Temperature is variable but may be as high as 5*.)3+. Sei<ures may occur. 0epatomegaly, Jaundice, anorexia, and weight loss can be marked.

&O(PLI&ATION)
$any complications have been described "Table 2#, of which gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy are the most important. Severe intestinal hemorrhage and intestinal perforation occur in '@'*A and *.)@2A of the patients, respectively. These and most other complications usually occur after the 'st week of the disease. 0emorrhage, which usually precedes perforation, is manifested by a decrease in temperature and blood pressure and an increase in the pulse rate. ,erforations, which are usually pinpoint si<e but may be as large as several centimeters, typically occur in the distal ileum and are accompanied by a marked increase in abdominal pain, tenderness, vomiting, and signs of peritonitis. Sepsis with various enteric aerobic gram-negative bacilli and anaerobes may develop. Although disturbed liver function test results are found for many patients with enteric fever, overt hepatitis and cholecystitis are considered complications. An increase in serum amylase levels may sometimes accompany clinically obvious pancreatitis. ,neumonia caused by superinfection with organisms other than Salmonella is more common in children than in adults. n children, pneumonia or bronchitis is common "approximately '*A#. Toxic myocarditis with fatty infiltration and necrosis of the myocardium may be

manifested by arrhythmias, sinoatrial block, ST-T changes on the electrocardiogram, or cardiogenic shock. Thrombosis and phlebitis occur rarely. %eurologic complications include increased intracranial pressure, cerebral thrombosis, acute cerebellar ataxia, chorea, aphasia, deafness, psychosis, and transverse myelitis. ,eripheral and optic neuritis have been reported. ,ermanent sequelae are rare. 8ther reported complications include fatal bone marrow necrosis, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis. Although osteomyelitis and suppurative arthritis can occur in a normal host, they are more common in children with hemoglobinopathies.

TABLE 3

DIA'NO)I)
+ulturing the Salmonella strain involved is usually the basis for confirming the diagnosis. 1esults of blood cultures are positive in 5*@6*A of the patients seen early in the course of the disease, and stool and urine cultures become positive "2)A to 2HA positive and approximately HA positive, respectively# after the 'st week. The stool culture result is also occasionally positive during the incubation period. /ecause of the intermittent and low-level bacteremia, repeated blood cultures should be obtained in suspect cases. +ultures of bone marrow often yield positive results during later stages of the disease, when blood cultures may be sterile& although seldom obtained, cultures of mesenteric lymph nodes, liver, and spleen may also have positive results at this point. A culture of bone marrow is the single most sensitive method of diagnosis "positive in I)@F*A# and is less influenced by prior

antimicrobial therapy. Stool and sometimes urine cultures are positive in chronic carriers. n suspected cases with negative results of stool cultures, a culture of aspirated duodenal fluid or of a duodenal string capsule may be helpful in confirming infection. 0owever, the duodenal string culture test cannot be performed on those too young or too ill to cooperate. !irect detection of S. ser. Typhi-specific antigens in the serum or S. ser. Typhi 9i antigen in the urine has been attempted by immunologic methods, often using monoclonal antibodies. !%A probes and polymerase-chain-reaction protocols have been developed to detect S. enterica serotype typhi directly in the blood. The methods are not yet widely used and are impractical in many areas where typhoid is common. ,olymerase chain reaction has been used to amplify specific genes of S. ser. Typhi in the blood of patients, enabling diagnosis within a few hours. This method is specific and more sensitive than blood cultures, given the low level of bacteremia in enteric fever. Serology is of little help in establishing the diagnosis, but it may be useful in epidemiologic studies. The role of ;idalKs test is controversial, because the sensitivity, specificity, and predictive values of this widely used test vary considerably among geographic areas. The test detects agglutinating antibodies to the 8 and 0 antigens of S. enterica serotype typhi. n acute infection, 8 antibody appears first, on days 6-I after the onset of the disease, rising progressively, later falling, and often disappearing within a few months "5-6 months#. 0 antibody appears slightly later, on days '*-'(, but persists longer "F months @ ( years# and can be used to distinguish between various types of enteric fever. =nfortunately, S. enterica serotype typhi shares these antigens with other salmonella serotypes and shares crossreacting epitopes with other .nterobacteriaceae. 4urthermore, patients with typhoid may mount no detectable antibody response or have no demonstrable rise in antibody titer. !espite this, some centers have found ;idalKs test helpful when it is used with locally determined cutoff points. There has been no consensus on the diagnostic titer for a single ;idal test. n ndonesia "especially in ,alembang#, a LMpositiveL ;idal test is based on a fourfold rise in 8 agglutinins in repeated tests or a titer of '7'6* or greater in a single test or an 0 agglutinin titer of '72(* or greater in single test. A 9i agglutination reaction has been used to screen for S. enterica serotype typhi carriers. ts reported sensitivity is H* to I* percent, with a specificity of I* to F) percent. %ewer serologic tests are being developed but do not yet perform well enough to ensure their widespread adoption. A normochromic, normocytic anemia often develops after several weeks of illness and is related to intestinal blood loss or bone marrow suppression. /lood leukocyte counts are frequently low in relation to the fever and toxicity, but there is a wide range in counts& leukopenia, usually not less than (,)** cells>mm 2 , is often found after the 'st or (nd week of illness. ;hen pyogenic abscesses develop, leukocytosis may reach (*,***@(),***>mm 2 . Thrombocytopenia may be striking and persist for as long as ' wk. Giver function test results are often disturbed. ,roteinuria is common. 4ecal leukocytes and fecal blood are very common.

DIFFERENTIAL DIA'NO)I)
!uring the initial stage of enteric fever, the clinical diagnosis may mistakenly be gastroenteritis, viral syndrome, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosis includes sepsis with other bacterial pathogens& infections caused by intracellular microorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsial diseases& viral infections, such as infectious mononucleosis and anicteric hepatitis& and malignancies, such as leukemia and lymphoma.

TREAT(ENT
Antimicrobial therapy is essential in treating enteric fever. /ecause of increasing antibiotic resistance, however, choosing the appropriate empirical therapy is problematic and controversial. Although antibiotic resistance of S. ser. Typhi isolates in the =nited States is relatively low "2@5A#, most infections are acquired abroad, where resistance occurs.

ncreasing rates of plasmid-mediated antibiotic resistance of S. ser. Typhi have been reported from Southeast Asia, $exico, and certain countries in the $iddle .ast. 1eports from ndia describe multiresistance to chloramphenicol, ampicillin, and T$,-S$N in 5F@I2A of S. ser. Typhi isolates. 1esistant strains are usually susceptible to third-generation cephalosporins. There is strong evidence that the fluoroquinolones are the most effective drugs for the treatment of typhoid fever. n randomi<ed, controlled trials involving patients infected by quinolone-susceptible S. enterica serotype typhi, these drugs have proved safe in all age groups and are rapidly effective even with short courses of treatment "three to seven days#. The average fever-clearance time is less than four days, and the cure rates exceed F6 percent. Gess than ( percent of treated patients have persistent fecal carriage or relapse "Table 5#. Ouinolones are efficacious but are not approved for children. $ost antibiotic regimens are associated with a )@(*A recurrence risk. +hloramphenicol "H)-'** mg>kg>(5 hr divided qid ,8 or 9#, ampicillin "(**mg>kg>(5hr divided q 5@6 hr 9#, amoxicillin "'** mg>kg>(5 hr divided tid ,8#, and trimethoprim-sulfamethoxa<ole "'* mg of T$, and )* mg of S$P>kg>(5 hr divided bid ,8# have demonstrated good clinical efficacy. Although chloramphenicol therapy is associated with a more rapid defervescence and sterili<ation of blood, the rate of relapse is somewhat higher, and this agent can cause potentially serious adverse effects. $ost children become afebrile within H days& treatment of uncomplicated cases should be continued for at least '5 days, or )@H days after defervescence. !ata suggest that very short courses of therapy may be adequate with oral cefixime "'*-') mg>kg>(5 hr divided bid for '* days#, ceftriaxone "I*mg>kg>(5hr once daily $ for ) days# or oral ofloxacin "') mg>kg>(5 hr for ( days#. +hloramphenicol remains the gold standard. n adults, ciprofloxacin at a dose of )**mg bid for H@'* days is effective and associated with a low relapse rate. n children with suspected resistant strains, empirical therapy with ceftriaxone "or cefotaxime# is appropriate until antibiotic susceptibility patterns are available. n addition to antibiotic therapy, a short course of dexamethasone "2 mg>kg for the initial dose, followed by 'mg>kg q 6hr for 5Ihr# improves the survival rate of patients with shock, obtundation, stupor, or coma. Supportive treatment and maintenance of appropriate fluid and electrolyte balance are essential. ;hen intestinal hemorrhage is severe, blood transfusion is needed. Surgical intervention and broad-spectrum antibiotics are recommended for intestinal perforation. Surgical resection of '*cm on each side of the perforation has been reported to improve survival. ,latelet transfusions have been suggested for the treatment of thrombocytopenia that is sufficiently severe to cause intestinal hemorrhage in patients for whom surgery is contemplated. Although attempts to eradicate chronic carriage of S. ser. Typhi are recommended for public health considerations, eradication is difficult despite in vitro susceptibility to the usual antibiotics. A course of 5@6 wk of high-dose ampicillin "or amoxicillin# plus probenecid or T$,-S$P results in an approximately I*A cure rate of carriers if no biliary tract disease is present. +iprofloxacin has been used successfully in adults. n the presence of cholelithiasis or cholecystitis, antibiotics alone are unlikely to be successful& cholecystectomy within '5 days of antibiotic treatment is recommended.

PRO'NO)I)
The prognosis for a patient with enteric fever depends on prompt therapy, the age of the patient, previous state of health, the causative Salmonella serotype, and the appearance of complications. n developed countries, with appropriate antimicrobial therapy, the mortality rate is less than 'A. n developing countries, the mortality rate is higher than '*A, usually because of delays in diagnosis, hospitali<ation, and treatment. nfants and children with underlying debilitating disorders are at higher risk. An uneventful recovery without antimicrobial therapy usually occurs in immunocompetent children with Salmonella gastroenteritis. Qoung infants and immunocompromised patients, particularly those with focal infection after bacteremia, can have prolonged, complicated courses. Salmonella meningitis has a poor prognosis and high relapse rate, particularly if treated with a short course of

therapy. The appearance of complications, such as gastrointestinal perforation or severe hemorrhage, meningitis, endocarditis, and pneumonia, is associated with high morbidity and mortality rates.

TABLE 4

.ven with appropriate therapy, patients can have recurrence of typhoid fever after completion of therapy ")A to (*A relapse rate#. 1elapses of Salmonella infections presumably reflect the difficulty in killing intraphagocytic organisms. /ecause relapse sometimes is due to resistant organisms, an agent different from the initial drug should be used empirically during the wait for culture results. n patients who have received appropriate antimicrobial therapy, the clinical manifestations of relapse become apparent about ( wk after stopping antibiotics and resemble the acute illness. The relapse, however, is usually milder and of shorter duration. %umerous relapses may occur. ndividuals who excrete S. ser. Typhi for R2 mo after infection usually become chronic carriers. The risk of becoming a carrier is low in children and increases with age& of all patients with typhoid fever, '@)A become chronic carriers. The incidence of biliary tract diseases is higher in chronic carriers than in the general population. Although chronic urinary carriage may also occur, it is rare and found mainly in individuals with schistosomiasis.

PREVENTION
n endemic areas, improved sanitation and clean running water are essential to control enteric fever. To minimi<e person-to-person transmission and food contamination, personal hygiene measures, handwashing, and attention to food preparation practices are necessary. .fforts to eradicate S. ser. Typhi from carriers are recommended, because humans are the only reservoir of S. ser. Typhi. ;hen such efforts are unsuccessful, carriers should be prevented from working in food- or water-processing activities, in kitchens, and in occupations related to patient care. These individuals should be made aware of the potential contagiousness of their condition and of the importance of handwashing and attentive personal hygiene. %o vaccine against nontyphoidal Salmonella infections is currently available, although two vaccines are available for S. typhi "Table 2#. They have similar efficacy, generally in the range
TABLE 1-- V!ccine$ for Prevention of Salmonella typhi V!ccine Or! ive !tten"!ted Ty*1! v!ccine -Vivotif Bern!0 ,rimary series /ooster "every ) yrs# Vi c!p$" !r po y$!cch!ride v!ccine -Typhim Vi0 ,rimary series /ooster "every ( yrs# Abbreviations: $, intramuscular. A single dose of *.)* mG "() Tg# $ A single dose of *.)* mG "() Tg# $ S(yr ' enteric-coated capsule every ( days for 5 doses ' enteric-coated capsule every ( days for 5 doses *@'A fever, '.)@2A headache, HA redness or induration at inJection site A%e Indic!ted R6yr Do$e !nd Ro"te Adver$e Re!ction$ *@)A fever or headache

of )*A to H)A for reducing the number of laboratory-confirmed cases within ( to 2 years. Seven-year follow-up data with enteric-coated capsules containing Ty('a live vaccine suggest greater than 6*A long-term protection. The live-attenuated vaccine should not be used in immunocompromised hosts or in persons receiving antibiotics at the time of

immuni<ation. Typhoid vaccination is recommended to travelers to endemic areas, especially Gatin America, Southeast Asia, and Africa. Such travelers need to be cautioned that the vaccine is not a substitute for personal hygiene and careful selection of foods and drinks, because none of the vaccines has efficacy approaching '**A. 4or typhoid vaccine live oral Ty('a "9ivotif#, immuni<ation should be completed at least ' week before possible exposure. 4or Typhim 9i, vaccine should be given at least ( weeks before possible exposure. 9accination is also recommended to individuals with intimate exposure to a documented carrier and for control of outbreaks. ,ediatric use of typhoid vaccines is limited to children who "'# will travel in areas where prolonged exposure to S. typhi is likely, "(# live where multiple-drug-resistant strains are prevalent, or "2# are members of households of documented carriers.