Typhoid Fever

Christopher M. Parry, M.B., Tran Tinh Hien, M.D., Gordon Dougan, Ph.D., Nicholas J. White, M.D., D.Sc., and Jere y J. !arrar, M.B., D.Phil.
Typhoid fever is a systemic infection with the bacterium Sal onella enterica serotype typhi. This highly adapted, human-specific pathogen has evolved remarkable mechanisms for persistence in its host that help to ensure its survival and transmission. Typhoid fever was an important cause of illness and death in the overcrowded and unsanitary urban conditions of the United States and Europe in the 1 th century.1 The Letters provision of clean water and good sewage systems led to a dramatic decrease in the incidence of typhoid in Add to Personal Archive these regions. Today most of the burden of the disease Add to Citation Manager occurs in the developing world, where sanitary conditions remain poor. !eliable data from which to Notify a Friend estimate the burden of disease in these areas are E-mail hen Cited difficult to obtain, since many hospitals lack facilities for blood culture and up to " percent of patients with Pu!Med Citation typhoid are treated as outpatients. #ommunity-based studies have consistently shown higher levels of typhoid than public health figures suggest. $nnual incidence rates of 1 % per 1"",""" in the &ekong 'elta region of (ietnam) and %" per 1"",""" in 'elhi, *ndia,+ have recently been reported. $ccording to the best global estimates, there are at least 1, million new cases of typhoid fever each year, with ,"",""" deaths.- The introduction of chloramphenicol for the treatment of typhoid fever in 1 -% transformed a severe, debilitating, and often fatal disease into a readily treatable condition.. The emergence of resistance to chloramphenicol and other antimicrobial agents has been a ma/or setback., 0e now face the very real prospect that untreatable typhoid fever will reemerge. Typhoid is usually contracted by ingestion of food or water contaminated by fecal or urinary carriers e1creting S. enterica serotype typhi. *t is a sporadic disease in developed countries that occurs mainly in returning travelers, with occasional pointsource epidemics.2 *n endemic areas, identified risk factors for disease include eating food prepared outside the home, such as ice cream or flavored iced drinks from street vendors,%, drinking contaminated water,1" having a close contact or relative with recent typhoid fever,%,11 poor housing with inade3uate facilities for personal hygiene,1) and recent use of antimicrobial drugs.

The Bacterium
S. enterica serotype typhi is a member of the family Enterobacteriaciae. The bacterium is serologically positive for lipopolysaccharide antigens 4 and 41), protein flagellar antigen 5d, and polysaccharide capsular antigen (i. The (i capsular antigen is largely restricted to S. enterica serotype typhi, although it is shared by some strains of S. enterica serotypes hirschfeldii 6paratyphi #7 and dublin, and Citro"acter #reundii. $ uni3ue flagella type, 5/, is present in some S. enterica serotype typhi isolates from *ndonesia.1+ 8hage typing, pulse-field gel electrophoresis, and ribotyping

have shown that areas of endemic disease usually have many strains in circulation but that outbreaks are usually due to a restricted number of strains.1-,1.,1, The Genome !ecently, the complete genome se3uence was determined for a multidrug-resistant strain of S. enterica serotype typhi 6#T1%7, which was isolated in 1 + from a child with typhoid fever in the &ekong 'elta region of (ietnam.12 The #T1% genome harbors -,%" ,"+2 base pairs with an estimated -. coding se3uences. The genomes of S. enterica serotype typhi #T1%, S. enterica serotype typhimurium 9T),1% and $scherichia coli1 are essentially collinear, despite the fact that $. coli and S. enterica diverged about 1"" million years ago. Similar environmental re3uirements for these enteric bacteria presumably e1plain this conservation of gene order. :ene clusters uni3ue to particular bacteria are likely to represent adaptations to particular environments or may contribute to pathogenicity. Unlike $. coli, S. enterica serotype typhi has several large insertions in its genome, termed salmonella pathogenicity islands, that are thought to be recent hori;ontal ac3uisitions and that encode genes important for survival in the host. *n addition, there are multiple insertions of many smaller gene blocks and individual genes scattered in the genome that may potentially be involved in pathogenicity 6<igure 17. Figure 1. :enetic Similarity of Sal onella enterica Serotype Typhi and $scherichia coli. The outer circle shows known and potential salmonella pathogenicity islands 6green7 and prophage 6gray7. The ne1t two circles inward show genes conserved between S. enterica serotype typhi and $. coli 6blue7 and genes uni3ue to S. View larger version enterica serotype typhi 6red7, transcribed in the clockwise and 6- =7> counterclockwise directions. The fourth circle shows ?in this window@ pseudogenes in brown. The black circle shows guanine and ?in a new window@ cytosine 6:A#7 content graphically, relative to the chromosomal average, and the inner circle graphically shows :B# skew, defined as 6:C#7B6:A#7. 4live indicates :B# skew of one or more, and purple :B# skew of less than one. 6#ourtesy of 'r. Dulian 8arkhill, Sanger #entre, #ambridge, United =ingdom.7 $ striking feature of the S. enterica serotype typhi genome is the presence of )"pseudogenes, more than half of which are inactivated by the introduction of a single frame-shift or stop codon, suggesting that they are of recent origin. $ substantial number are predicted to be involved in housekeeping functions or in virulence or host interactions. This apparent inactivation of genes responsible for host interactions may e1plain why S. enterica serotype typhi, unlike other salmonella serotypes, is restricted to one host 6i.e., humans7 and suggests that S. enterica serotype typhi may have passed through a recent evolutionary bottleneck. S. enterica serotype typhi #T1% harbors two plasmids. The larger con/ugative plasmid, p5#&1, is )1% kb in length and shares appro1imately 1,% kb of 'E$ with

the plasmid !)2, with more than percent se3uence identity.)" !)2 is an inc51 plasmid, first isolated in the 1 ,"s from S. enterica, that is closely related to the chloramphenicol-resistance plasmids detected in S. enterica serotype typhi in the 1 2"s.)1 The p5#&1 plasmid encodes resistance to chloramphenicol 6cat% 7, ampicillin 6TE&-1, "la7, trimethoprim 6dh#r1b7, sulfonamides 6sul **7, and streptomycin 6str$F7. The smaller plasmid, p5#&), is 1",.. kb in length and is phenotypically cryptic, but it has striking homology with the p&T1 virulenceassociated plasmid of &ersinia pestis. Pathogenesis The infectious dose of S. enterica serotype typhi in volunteers varies between 1""" and 1 million organisms.)) (i-negative strains of S. enterica serotype typhi are less infectious and less virulent than (i-positive strains. S. enterica serotype typhi must survive the gastric acid barrier to reach the small intestine, and a low gastric p5 is an important defense mechanism. $chlorhydria as a result of aging, previous gastrectomy, or treatment with histamine 5)-receptor antagonists, proton-pump inhibitors, or large amounts of antacids lowers the infective dose. *n the small intestine, the bacteria adhere to mucosal cells and then invade the mucosa. The & cells, speciali;ed epithelial cells overlying 8eyerGs patches, are probably the site of the internali;ation of S. enterica serotype typhi and its transport to the underlying lymphoid tissue. $fter penetration, the invading microorganisms translocate to the intestinal lymphoid follicles and the draining mesenteric lymph nodes, and some pass on to the reticuloendothelial cells of the liver and spleen. Salmonella organisms are able to survive and multiply within the mononuclear phagocytic cells of the lymphoid follicles, liver, and spleen.)+ $t a critical point that is probably determined by the number of bacteria, their virulence, and the host response, bacteria are released from this se3uestered intracellular habitat into the bloodstream. The incubation period is usually 2 to 1- days. *n the bacteremic phase, the organism is widely disseminated. The most common sites of secondary infection are the liver, spleen, bone marrow, gallbladder, and 8eyerGs patches of the terminal ileum. :allbladder invasion occurs either directly from the blood or by retrograde spread from the bile. 4rganisms e1creted in the bile either reinvade the intestinal wall or are e1creted in the feces. #ounts of bacteria in patients with acute typhoid fever indicate a median concentration of 1 bacterium per milliliter of blood 6about ,, percent of which are inside phagocytic cells7 and about 1" bacteria per milliliter of bone marrow.)-,).,), Even though S. enterica serotype typhi produces a potent endoto1in, mortality from treated typhoid fever for patients at this stage is less than 1 percent. Studies have shown increased levels of circulating proinflammatory and antiinflammatory cytokines in patients with typhoid and a reduced capacity of whole blood to produce inflammatory cytokines in patients with severe disease.)2,)%,) Typhoid induces systemic and local humoral and cellular immune responses, but these confer incomplete protection against relapse and reinfection. The interaction of host immunologic mediators and bacterial factors in infected tissue may contribute to the necrosis of 8eyerGs patches in severe disease.+" The evidence for an association between typhoid and infection with the human immunodeficiency virus 65*(7 is conflicting,+1,+) whereas there is a large increase in the incidence of non-typhi salmonella bacteremia in 5*( infection. &a/or-histocompatibility-comple1 class **

and class *** alleles have been shown to be associated with typhoid fever in (ietnam. 59$-'!F1H"+"1B,B%, 59$-'IF1H")"1-+, and TE<$H)6C+"%7 were found to be associated with susceptibility to typhoid fever, whereas 59$-'!F1H"-, 59$'IF1H"-"1B), and TE<$H16C+"%7 were associated with disease resistance.++ 8olymorphisms in the genes encoding the natural-resistanceCassociated macrophage protein were not associated with resistance to typhoid, in contrast to the importance of this allele in the murine model.+Antimicrobial Resistance *n 1 -% chloramphenicol became the standard antibiotic for treating typhoid.. $lthough resistance emerged within two years after its introduction, it was not until 1 2) that chloramphenicol-resistant typhoid fever became a ma/or problem., 4utbreaks occurred in &e1ico, *ndia, (ietnam, Thailand, =orea, and 8eru., #hloramphenicol resistance was associated with high-molecular-weight, selftransferable, %nc5* plasmids. These S. enterica serotype typhi strains were also resistant to sulfonamides, tetracycline, and streptomycin, but initially amo1icillin and trimethoprimCsulfametho1a;ole remained effective alternative drugs. Toward the end of the 1 %"s and the 1 "s, S. enterica serotype typhi developed resistance simultaneously to all the drugs that were then used as first-line treatment 6chloramphenicol, trimethoprim, sulfametho1a;ole, and ampicillin7., 4utbreaks of infections with these strains occurred in *ndia,+.,+, 8akistan,+2,+% Fangladesh,+ (ietnam,-" the &iddle East,-1 and $frica-) 6<igure )7. These multidrug-resistant strains also carried the 1"","""-to-1)","""-k' %nc5* plasmids that encoded the resistance genes. Spread results from the clonal dissemination of individual multidrug-resistant S. enterica serotype typhi strains or from transfer of the plasmid to multiple S. enterica serotype typhi strains.1-,1.,1, !esistance rarely emerges during the course of treatment.-+ &ultidrug-resistant S. enterica serotype typhi are still common in many areas of $sia, although in some areas strains that are fully susceptible to all first-line antibiotics have reemerged.-Figure 2. :lobal 'istribution of !esistance to Sal onella enterica Serotype Typhi, 1 " through )""). $ll shaded areas are areas of endemic disease. View larger version 6+"=7> ?in this window@ ?in a new window@

There have been sporadic reports of high-level resistance to ceftria1one 6minimal inhibitory concentration ?&*#@, ,- mg per liter7 in S. enterica serotype typhi and S. enterica serotype paratyphi $,-.,-, although these strains are very rare. S. enterica serotype typhi strains with reduced susceptibility to fluoro3uinolones have become a ma/or problem in $sia.-2,-%,- ,." $n outbreak of typhoid with such strains in Ta/ikistan in 1 2 sickened %""" people in a si1-month period and caused 1." deaths.1" $lthough they were reported to be susceptible to fluoro3uinolones, by disk testing

with the use of recommended break points, these organisms were resistant to nalidi1ic acid and the &*# of fluoro3uinolones for these strains was 1" times that for fully susceptible strains. This reduction in susceptibility results in a poor clinical response to treatment.-%,- Iuinolone resistance is fre3uently mediated by single point mutations in the 3uinolone-resistanceCdetermining region of the gyr$ gene, characteristically occurring at position %+ of the 'E$ gyrase en;yme 6changing serine to phenylalanine7 and position %2 6changing aspartate to tyrosine or glycine7.-2,-% Iuinolones, such as nalidi1ic acid, are a group of synthetic compounds based on the --3uinolone nucleus. The introduction of fluorine at position , of the nucleus creates the fluoro3uinolone group of compounds, which have substantially greater antimicrobial activity. *n other Enterobacteriaciae, higher levels of 3uinolone resistance have been associated with additional mutations in the gyr$ gene, mutations in other topoisomerase genes, or alterations in fluoro3uinolone uptake. Eo such mutations have been reported yet in S. enterica serotype typhi, although there are sporadic reports of fully fluoro3uinolone-resistant isolates..1 Fecause the clinical response to fluoro3uinolones in patients infected with nalidi1ic acidCresistant strains is greatly inferior to the response in those infected with nalidi1ic acidCsusceptible strains, we believe that the break points for the classification of S. enterica serotype typhi strains according to their susceptibility to fluoro3uinolones should be changed.." $ pragmatic solution would be to classify strains that are resistant to nalidi1ic acid but susceptible to fluoro3uinolones according to current disk-testing criteria as resistant to 3uinolones or nonsusceptible to fluoro3uinolones. $ll strains that have intermediate susceptibility or resistance to fluoro3uinolones on disk testing 6as defined by national guidelines7 should be considered fluoro3uinolone-resistant.

Clinical Features
The clinical manifestations and severity of typhoid fever vary with the patient population studied. &ost patients who present to hospitals with typhoid fever are children or young adults from . to ). years of age.1,.),.+ 5owever, community-based studies in areas of endemic disease indicate that many patients with typhoid, particularly children under five years of age, may have a nonspecific illness that is not recogni;ed clinically as typhoid.),+,.- Fetween ," and " percent of people with typhoid do not receive medical attention or are treated as outpatients.),+ $fter a person ingests S. enterica serotype typhi, an asymptomatic period follows that usually lasts 2 to 1- days 6range, + to ,"7. The onset of bacteremia is marked by fever and malaise. 8atients typically present to the hospital toward the end of the first week after the onset of symptoms with fever, influen;a-like symptoms with chills 6although rigors are rare7, a dull frontal headache, malaise, anore1ia, nausea, poorly locali;ed abdominal discomfort, a dry cough, and myalgia, but with few physical signs.1,+2,.),.+,.. $ coated tongue, tender abdomen, hepatomegaly, and splenomegaly are common. $ relative bradycardia is considered common in typhoid, although in many geographic areas this has not been a consistent feature. $dults often have constipation, but in young children and in adults with 5*( infection, diarrhea is more common.+1,., *t is unusual for a patient hospitali;ed with typhoid to have no abdominal symptoms and normal bowel movements. *nitially the fever is low grade, but it rises progressively, and by the second week it is often high and sustained 6+ J to -"J#7. $ few rose spots, blanching erythematous maculopapular lesions appro1imately ) to - mm in diameter,

are reported in . to +" percent of cases. They usually occur on the abdomen and chest and more rarely on the back, arms, and legs. These lesions are easily missed in darkskinned patients. There may be a history of intermittent confusion, and many patients have a characteristic apathetic affect. #onvulsions may occur in children under five years of age... The hemoglobin level, white-cell count, and platelet count are usually normal or reduced. 'isseminated intravascular coagulation may be revealed by laboratory tests, but it is very rarely of clinical significance. The levels of liver en;ymes are usually two to three times the upper limit of normal. #omplications occur in 1" to 1. percent of patients and are particularly likely in patients who have been ill for more than two weeks. &any complications have been described 6Table 17, of which gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy are the most important. :astrointestinal bleeding is the most common, occurring in up to 1" percent of patients. *t results from erosion of a necrotic 8eyerGs patch through the wall of an enteric vessel. *n the ma/ority of cases, the bleeding is slight and resolves without the need for blood transfusion, but in ) percent of cases, bleeding is clinically significant and can be rapidly fatal if a large vessel is involved. *ntestinal 6usually ileal7 perforation is the most serious complication, occurring in 1 to + percent of hospitali;ed patients..2,.% 8erforation may be manifested by an acute abdomen or, more covertly, by simple worsening of abdominal pain, rising pulse, and falling blood pressure in an already sick patient. $ reduced level of consciousness or encephalopathy, often accompanied by shock, is associated with high mortality.. ,,",,1 The patient is commonly apathetic although rousable. 8atients can be severely agitated, delirious, or obtunded, but complete stupor or coma is infre3uent. The incidence of these neuropsychiatric presentations varies among countries. *t ranges from 1" to -" percent among hospitali;ed patients with typhoid in *ndonesia. ,," and 8apua Eew :uinea,1 but is less than ) percent in 8akistan+2 and (ietnam.-" This geographic variation is une1plained. Typhoid fever during pregnancy may be complicated by miscarriage, although antimicrobial treatment has made this outcome less common.,) (ertical intrauterine transmission from an infected mother may lead to neonatal typhoid, a rare but severe and life-threatening illness.,+ View this table: Table 1. *mportant #omplications of Typhoid <ever. ?in this window@ ?in a new window@

!elapse occurs in . to 1" percent of patients, usually two to three weeks after the resolution of fever. The relapse is usually milder than the original attack, and the S. enterica serotype typhi isolate from a patient in relapse usually has the same antibiotic-susceptibility pattern as the isolate obtained from the patient during the original episode. !einfection may also occur and can be distinguished from relapse by molecular typing.+ ,,- Up to 1" percent of convalescing patients with untreated typhoid e1crete S. enterica serotype typhi in the feces for up to three monthsK 1 to - percent become long-term carriers, e1creting the organism for more than one year. Up to ). percent of long-term carriers have no history of typhoid. #hronic carriage is more common among women and the elderly and in patients with cholelithiasis.,. &ost

carriers are asymptomatic. 8atients with an abnormal urinary tract, such as those who have schistosomiasis, may e1crete the organism in the urine for long periods. The average case fatality rate is less than 1 percent, but the rate varies considerably among different regions of the world. $mong hospitali;ed patients, the case fatality rate varies from less than ) percent in 8akistan+2 and (ietnam-" to +" to ." percent in some areas of 8apua Eew :uinea,1 and *ndonesia.. ,," The case fatality rates are highest among children under one year of age and among the elderly.+2,.),.. 5owever, the most important contributor to a poor outcome is probably a delay in instituting effective antibiotic treatment.

Management
Diagnosis The absence of specific symptoms or signs makes the clinical diagnosis of typhoid difficult. *n areas of endemic disease, a fever without evident cause that lasts more than one week should be considered typhoid until proved otherwise. Flood cultures are the standard diagnostic methodK provided a large volume of blood is cultured 61. ml in adults7, they are positive in ," to %" percent of patients with typhoid. #ulture of bone marrow is more sensitive. The result is positive in %" to . percent of patients with typhoid, even patients who have been taking antibiotics for several days, regardless of the duration of illness.),,,,,,2,,% Flood cultures are less sensitive than bone marrow cultures because of the lower numbers of microorganisms in blood as compared with bone marrow.).,), The sensitivity of blood culture is higher in the first week of the illness, is reduced by prior use of antibiotics, and increases with the volume of blood cultured and the ratio of blood to broth. #ultures have also been made from the buffy coat of blood,, streptokinase-treated blood clots,,% intestinal secretions 6with the use of a duodenal string capsule7,,2 and skin snips of rose spots.,, The sensitivity of stool culture depends on the amount of feces cultured, and the positivity rate increases with the duration of the illness. Stool cultures are positive in +" percent of patients with acute typhoid fever. <or the detection of carriers, several samples should be e1amined because of the irregular nature of shedding. The role of 0idalGs 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 4 and 5 antigens of S. enterica serotype typhi. Unfortunately, S. enterica serotype typhi shares these antigens with other salmonella serotypes and shares cross-reacting epitopes with other Enterobacteriaceae. <urthermore, patients with typhoid may mount no detectable antibody response or have no demonstrable rise in antibody titer. 'espite this, some centers have found 0idalGs test helpful when it is used with locally determined cutoff points.2",21 $ (i agglutination reaction has been used to screen for S. enterica serotype typhi carriers. *ts reported sensitivity is 2" to %" percent, with a specificity of %" to . percent.2) Eewer serologic tests are being developed but do not yet perform well enough to ensure their widespread adoption.2+,2- 'E$ probes and polymerase-chainreaction protocols have been developed to detect S. enterica serotype typhi directly in the blood.2. The methods are not yet widely used and are impractical in many areas where typhoid is common.

Typhoid must be distinguished from other endemic acute and subacute febrile illnesses. &alaria, deep abscesses, tuberculosis, amebic liver abscess, encephalitis, influen;a, dengue, leptospirosis, infectious mononucleosis, endocarditis, brucellosis, typhus, visceral leishmaniasis, to1oplasmosis, lymphoproliferative disease, and connective-tissue diseases should be considered. <or patients in countries where typhoid is not endemic, a travel history is crucial. #linical algorithms have been developed but have not generally been validated. Treatment *n areas of endemic disease, more than ," to " percent of cases of typhoid fever are managed at home with antibiotics and bed rest. <or hospitali;ed patients, effective antibiotics, good nursing care, ade3uate nutrition, careful attention to fluid and electrolyte balance, and prompt recognition and treatment of complications are necessary to avert death. There is strong evidence that the fluoro3uinolones are the most effective drugs for the treatment of typhoid fever. *n randomi;ed, controlled trials involving patients infected by 3uinolone-susceptible S. enterica serotype typhi, these drugs have proved safe in all age groups and are rapidly effective even with short courses of treatment 6three to seven days7.2,,22,2%,2 ,%" The average fever-clearance time is less than four days, and the cure rates e1ceed , percent. 9ess than ) percent of treated patients have persistent fecal carriage or relapse 6Table ) and Supplementary $ppendi1 17. The published data also suggest that the fluoro3uinolones are more rapidly effective and are associated with lower rates of stool carriage than the traditional first-line drugs 6chloramphenicol and trimethoprimCsulfametho1a;ole7.2,,22 View this table: ?in this window@ ?in a new window@ Table 2. 8ooled 'ata from !andomi;ed, #ontrolled Trials of Treatment of Typhoid <ever.

#oncern has been e1pressed about three main issues regarding the use of fluoro3uinolones in the treatment of typhoid fever> the potential for to1ic effects in children, the cost, and the potential emergence of resistance. *n preclinical testing, the fluoro3uinolones damaged the articular cartilage of young beagles. There is now a considerable body of reassuring evidence from the long-term use of fluoro3uinolones in children with cystic fibrosis and from the short-term use of fluoro3uinolones to treat typhoid fever and of fluoro3uinolones or nalidi1ic acid to treat bacillary dysentery in children.%1,%),%+,%- There has been no evidence of bone or /oint to1icity, tendon rupture, or, in long-term follow-up, impairment of growth. The production of generic fluoro3uinolones in $sia has reduced the price considerably. 5owever, the emergence of 3uinolone resistance in areas where these drugs are ine1pensive and readily available is likely to be the greatest limitation on their use. <ortunately, full fluoro3uinolone resistance is still rare.

*n areas where 3uinolone-resistant strains are uncommon, the fluoro3uinolones are the current treatment of choice for all age groups 6Table +7. Short courses of treatment 6three to five days7 are particularly useful to contain epidemics. $mong patients with 3uinolone-resistant S. enterica serotype typhi infection, the rate of treatment failure is higher for those treated for less than seven days than for those treated for a longer period.-% Treatment at the ma1imal recommended doses 6e.g., )" mg of oflo1acin per kilogram of body weight per day7 for 2 to 1" days has been successful in " to . percent of patients with resistant infections. 5owever, the fever-clearance times are long 6seven days, on average7, and the rate of fecal carriage during convalescence can be as high as )" percent 6unpublished data7. <luoro3uinolones should be used at the ma1imal possible dose for a minimum of 1" to 1- days, and the patients should be carefully followed to determine whether they are e1creting S. enterica serotype typhi in their feces. Unfortunately, 3uinolone-resistant strains are often also multidrugresistant, and therefore the choice of drugs is limited to a;ithromycin or the cephalosporins, which are e1pensive. View this table: Table 3. Treatment of Uncomplicated Typhoid. ?in this window@ ?in a new window@

The third-generation cephalosporins 6ceftria1one, cefi1ime, cefota1ime, and cefopera;one7 and a;ithromycin are also effective drugs for typhoid. *n randomi;ed, controlled trials of third-generation cephalosporins, principally ceftria1one and cefi1ime, the fever-clearance times averaged one week and the rates of treatment failure were . to 1" percent.22,2%,%.,%, The relapse rates were + to , percent, and the fecal-carriage rates were less than + percent. #ure rates of . percent were achieved with five to seven days of treatment with a;ithromycin.2 ,%",%,,%2 <ever resolved in four to si1 days, and the rates of relapse and convalescent fecal carriage were less than + percent. $;treonam and imipenem are potential third-line drugs.2,,%% #hloramphenicol, amo1icillin, and trimethoprimCsulfametho1a;ole remain appropriate for the treatment of typhoid fever in areas of the world where the bacterium is still fully susceptible to these drugs and where the fluoro3uinolones are not available or affordable.% These drugs are ine1pensive, widely available, and rarely associated with side effects. They produce relief of symptoms, with defervescence usually occurring within five to seven daysK however, two to three weeks of treatment is re3uired, and adherence to a four-times-daily regimen over this period may be low. $n adult will often have to take more than )." capsules of chloramphenicol during a course of treatment. $lthough the cure rate is appro1imately . percent, the relapse rate is 1 to 2 percent, and the rate of convalescent e1cretion is ) to 1" percent. There are few data on the treatment of pregnant women with typhoid. The beta-lactam antibiotics are considered safe.,) *n addition, there have been several case reports of the successful use of fluoro3uinolones. " $lthough these drugs have generally been avoided because of concern about safety, the general consensus is that they are also safe. 1

&ost of the data from randomi;ed, controlled trials come from patients treated in regions where disease is endemic. There are few data from such trials of treatment in patients living in regions where the disease is not endemic or in returning travelers. =nowledge of the antibiotic susceptibility of the infecting strain is crucial in determining which drug to use. *f no culture is available, knowledge of the likely susceptibility from the available global data may be useful 6<igure )7. evere T!"hoi# The parenteral fluoro3uinolones are probably the antibiotics of choice for severe infections, but there have been no randomi;ed trials of such treatment. ) *n severe typhoid, the fluoro3uinolones are given for a minimum of 1" days 6Table -7. $dults and children with severe typhoid characteri;ed by delirium, obtundation, stupor, coma, or shock benefit from the prompt administration of de1amethasone. The mortality rate was reduced from over ." percent to 1" percent in *ndonesian adults and children who were given de1amethasone at an initial dose of + mg per kilogram by slow intravenous infusion over a period of +" minutes, followed by 1 mg of de1amethasone per kilogram given at the same rate every , hours for eight additional doses. 5ydrocortisone at a lower dose was not effective.. ,,",,1 View this table: Table $. Treatment of Severe Typhoid. ?in this window@ ?in a new window@

8atients with gastrointestinal perforation during typhoid re3uire resuscitation with fluids, blood, and o1ygen, as appropriate, followed by surgery..2,.% $t operation, the ileum, cecum, and pro1imal large bowel should be e1amined for perforations 6<igure +7. Several procedures can be performed, including intestinal resection and primary anastomosis or wedge resection or dLbridement of the ulcer, with primary closure of the perforation. $ temporary ileostomy or ileocolostomy is sometimes re3uired. The sites of impending perforation can be sutured with serosa-to-serosa appro1imation. 9avage of the peritoneal cavity should be followed by closure, with or without drainage. 8atients re3uire additional parenteral antibiotics to eliminate enteric aerobes and anaerobes that may contaminate the peritoneal cavity. Early intervention is crucial, and mortality rates increase as the delay between perforation and surgery lengthens. The mortality rate after perforation varies between 1" and +) percent..2,.% &any cases of intestinal hemorrhage are not severe and can be managed without transfusion, but blood should be cross-matched immediately and the surgical team alerted. Figure 3. :astrointestinal 8erforation. :astrointestinal perforation 6arrow7, usually of the terminal ileum or pro1imal large bowel, is one of the most serious complications of typhoid fever.

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!elapses should be treated in the same way as initial infections. The ma/ority of intestinal carriers can be cured by a prolonged course of antibiotics, provided they do not have gallstones. #ure rates of appro1imately %" percent have been achieved with 1"" mg of ampicillin or amo1icillin per kilogram per day, taken orally, with +" mg of probenecid per kilogram per day for + monthsK two tablets of trimethoprimC sulfametho1a;ole twice daily for + monthsK or 2." mg of ciproflo1acin twice daily for )% daysK the cure rate varies with the susceptibility of the organism.2,, + *n the presence of cholelithiasis, antibiotic therapy as well as cholecystectomy may be re3uired. *n patients with chronic urinary carriage resulting from infection with Schistoso a hae ato"iu , the schistosomiasis should be treated with pra;i3uantel before the S. enterica serotype typhi infection.

Control of Typhoid
*n developing countries, reducing the number of cases in the general population re3uires the provision of safe drinking water, effective sewage disposal, and hygienic food preparation.- &ass immuni;ation has been used successfully in some areas. - *n developed countries, identification of chronic carriers is now less important than formerly. &ost cases are the result of travel to areas of endemic disease. Travelers in such areas need to take particular care with food and water. 0ater for drinking should be boiled or bottled, food should be thoroughly cooked, and ice cream should be regarded with suspicion. <resh vegetables or fruits that have been washed in local water are potential sources of infection. The first parenteral whole-cell typhoid vaccine was introduced in 1% ,. *ts efficacy was established in field trials in the 1 ,"s in 8oland, Mugoslavia, :uyana, and the Soviet Union. . The various vaccines offered .1 to %% percent protection to children and young adults, lasting for up to 1) years. The chief disadvantages of the whole-cell vaccine are local discomfort and swelling and the systemic side effects that occur in ). to ." percent of recipients. . <ield studies of Ty)1a, a live, attenuated oral vaccine, have shown variable protective efficacy, ranging from , percent after + years in Egypt , to ,2 percent after . years in #hile 2 and -) to .+ percent, depending on the formulation, after ).. years in *ndonesia. % The vaccine is given as one capsule on days 1, +, ., and 2 and is suitable for adults and children over si1 years of age. $ booster dose is recommended every five years. The vaccine is well tolerated, but because it is a live, attenuated vaccine, it should not be given to immunocompromised patients or patients taking antibiotics. $lternative oral vaccines are at different stages of development. The parenteral (i-based vaccine is suitable for adults and children over the age of two years and has no serious side effects. $ single dose of ".. ml 6). Ng7 is administered intramuscularly. Fooster doses are recommended every two years. $ single in/ection of the (i vaccine provided a protective efficacy of 2) percent after 12 months in Eepal and ,- percent after )1 months in South $frica.1"" $ new modified (i vaccine con/ugated to a nonto1ic recombinant Pseudo onas aeruginosa e1oto1in $ 6rE8$7

was evaluated recently in (ietnam. *n an area where the incidence of typhoid in children two to five years of age was -1- cases per 1"",""" per year, the protective efficacy was 1.. percent.1"1 $n important advantage of this vaccine is that it has the potential to be immunogenic in infants under the age of two. There is no currently licensed vaccine against S. enterica serotype paratyphi $. The Ty)1a and (i vaccines are recommended for travelers to areas where typhoid is endemic, household contacts of typhoid carriers, and laboratory workers likely to handle S. enterica serotype typhi,- although there is no evidence from controlled trials that these vaccines are effective outside areas of endemic disease. *n areas where epidemic risk is high, mass immuni;ation should be considered during disasters or in refugee camps, in combination with ade3uate provision of safe water and food.1")

The Future
The ideal components of effective case management of typhoid fever in areas of endemic disease would be a reliable and ine1pensive diagnostic test and cheap, effective oral antibiotics. The lack of a simple diagnostic test O or, indeed, of any diagnostic facilities in many areas of endemic disease O means that typhoid is a disease whose importance is underestimated worldwide. #heap, effective oral antibiotics have been available for the past -" to ." years, but this situation is changing. The widespread emergence of multidrug-resistant typhoid in $frica will add an additional burden to an already overstretched health care system. The resources to pay for fluoro3uinolones or cephalosporins to treat resistant cases of typhoid in this region are scarce. The threat of the emergence of resistance to the remaining drugs used to treat typhoid is also very real. There are already sporadic reports of resistance to fluoro3uinolones and third-generation cephalosporins.-.,-,,.1 0hat could we recommend for the emergency treatment of a large outbreak caused by a multidrug and fully fluoro3uinolone-resistant strainP Strategies to avert this possibility need to be considered seriously. *mprovements in the provision of clean water and sanitation are critical to reduce the overall burden of typhoid, but such improvements will be slow. The use of combination chemotherapy, the evaluation of new drugs, and the wider use of vaccination in areas of endemic disease are options. *n Thailand, the incidence of typhoid was reduced dramatically by a program of yearly vaccination of schoolchildren with the old whole-cell vaccine. The emergence of antimicrobial resistance may change the balance of cost effectiveness for mass-vaccination programs in such areas, however. $ typhoidvaccination program for schoolchildren or, with the advent of the new con/ugate (i vaccine, as part of the E1panded 8rogram of *mmuni;ation, should be considered.
Supported by grants from the 0ellcome Trust. 'r. 0hite is a 0ellcome Trust 8rincipal <ellow, and 'r. <arrar is a 0ellcome Trust Senior #linical <ellow.

"ource #nformation
<rom the #entre for Tropical &edicine, Euffield 'epartment of #linical &edicine, University of 41ford, 41ford, United =ingdom 6#.&.8., E.D.0., D.D.<.7K the #entre for &olecular &icrobiology and *nfection, 'epartment of Fiological Sciences, *mperial #ollege of Science, Technology and &edicine, 9ondon 6:.'.7K the 5ospital for Tropical 'iseases, 5o #hi &inh #ity, (ietnam 6T.T.5.7K the

0ellcome TrustC&ahidol UniversityC41ford Tropical &edicine !esearch 8rogramme, <aculty of Tropical &edicine, &ahidol University, Fangkok, Thailand 6E.D.0.7K and the University of 41ford #linical !esearch Unit, 5ospital for Tropical 'iseases, 5o #hi &inh #ity, (ietnam 6D.D.<.7. $ddress reprint re3uests to 'r. <arrar at the University of 41ford #linical !esearch Unit, 5ospital for Tropical 'iseases, 1 " Fen 5am Tu, Iuan ., 5o #hi &inh #ity, (ietnam, or at /eremy/fQhcm.vnn.vn .

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Typhoid Fever van Doorn K. J., Pierard D., Verbeelen D., Basnyat B., Zaidi A. K.M., Hasan R., Bhutta Z. A., Parry C. M., Hien T. T., hite !. J., "arrar J. J. #$tra%t & "ull Te$t & PD" ! #n'l J Med ())*+ *,-.//-(0//-,, Mar (), ())*. Correspondence

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Analisis realibilitas tes wi#al #an tube3 untu4 "emeri4saan serologi #emam ti)oi#
!eliability $nalysis of 0idal and Tube1 Tests for !apid Serologic Test of Typhoid <ever 4leh > Tri &ur 0ristina+ 5en#ro 6ah7ono+ uba4ir+ T7ah7at 2ntro#uction: #linical symptoms of typhoid fever van, widely and not always specific. Serologic tests would be useful in areas with limited capability of laboratory to diagnose typhoid fever. Tube1 is a rapid and simple new serology diagnostic, and reported as a specific test to detect anti-Salmonella " Bg&. 5owever, Tube1 is more e1pensive than 0idal test that has been widely used for diagnosis of typhoid fever but considered not reliable enough especially when used in endemic areas. 0e e1amined

the perfomiance of Tube1 test in tertiary hospital settings, and compared it with 0idal test. The result of this study would be useful to make decision on the usefulness of new serology test. *etho#s: This was a diagnostic study in which blood samples from ++ patients with fever for + days or more were collected for serologic testing to assess the 9&dal and Tube1 test. =appa test was used to determine the reliability between the ) methods. Results: #ompared with Tube1, with cut-off value for the 0idal test anti-T4 titer is 1B1,", the =appa value was ".,". Eevertheless, when cut-off values is 1B%", the =appa value increased to "., . *t means that in an endemic area, which uses 0idal test anti T4 titer with cut-off value 1B1," or waiting for increasing titer 6paired sera7 as a significance diagnosis, Tube1 test can detects acute typhoid feverearlierthan 0idal. 8onclusions: Tube1 test is likely to be useful for early detection of an acute phase of lyp hold fever. Therefore, patients can immediately receive appropriate antimicrobial therapy. 0e!wor#s : Typhoid fever, 0idal, Tube1

VVVVVVVVVVVVVVVVVVVVVVVV Pen#ahuluan: :e/ala klinis demam typhoid sangat bervariasi dan tidak selalu spesifik. 8emeriksaan serologi berguna untuk mendiagnosis demam tifoid di daerah dengan keterbatasan kemampuan laboratorium. Tube1 adalah pemeriksaan serologi baru yang cepat dan mudah serta bersifat spesifik dalam mendeteksi anti-Salmonella " Bg&. &eski demikian Tube1 lebih mahal daripada 0idal yang telah digunakan secara luas dntuk mendiagnosa demam typhoid, walaupun diderah endemik rellabilitasnya kurang dapat dipercaya. 8enelitian ini membandingkan antara Tube1 dengan 0idal di !S tertier. 5asil penelitian diharapkan berguna untukmempertimbangkan penggunaan tes serologi yang baru. *eto#e: &erupakan penelitian diagnostik, yaitu sampel darah dan ++ pasien dengan demam + hari atau lebih dilakukan pemeriksaan tes 0idal dan Tube1. Tes =appa digunakan untuk mengukur reliabilitas antara ke ) metode tersebut. 5asil: 8eneiltian ini menghasilkan nllai =appa ",," pada perbandingan tes Tube1 dengan tes 0idal yang menggunakan kriteria 6A7 anti-T4 titer 1B1,". =etika menggunakan kriteria 6A7 dan tes 0idal dengan anti-T4 titer 1B%", maka nilai =appa meningkat men/adi ",, . 5al ini berarti bahwa pada daerah endemik dimana digunakan kriteria 6A7 bila tes 0idal anti T4 titer WV 1B1," atau menunggu adanya kenaikan titer 6paired sera7, tes Tube1 dapat mendeteksi demam tifoid akut lebih awal datipada 0idal im"ulan: Tes Tube1 tampaknya berguna untuk deteksi dini infeksi akut demam tifoid. 4leh karena itu pengobatan antimikroba yang adekwat dapat segera diberikan.

VVVVVVVVVVVVVVVVVVVVVVVV catatan : 'okumen di situs Durnal =edokteran &edia &edika *ndonesiana ini direproduksi dari naskah cetak asli dengan teknik 4#! 64nline #haracter !ecognition7. 8engelola mohon maaf apabila ter/adi kesalahan ketik atau e/aan yang mungkin tidak ter/adi di naskah aslinya. Eamun demikian akan dilakukan perbaikan terus menerus /ika ditemukan kesalahan ketik atau e/aan dikemudian hari