INTRODUCTION — Enteric fever is characterized by severe systemic illness with fever and abdominal pain . The organism classically responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi (formerly S. typhi). Other Salmonella serotypes, particularly S. enterica serotypes Paratyphi A, B, or C, can cause a similar syndrome; however, it is usually not clinically useful or possible to reliably predict the causative organism based on clinical findings . The term "enteric fever" is a collective term that refers to both typhoid and paratyphoid fever, and "typhoid" and "enteric fever" are often used interchangeably.
The treatment and prevention of enteric fever will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of enteric fever are discussed separately. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
ANTIMICROBIAL RESISTANCE — Treatment of enteric fever has been complicated by the development and rapid global spread of typhoidal organisms resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. Additionally, development of increasing resistance to fluoroquinolones and cephalosporins is a growing challenge.
Fluoroquinolone resistance — Historically, resistance to the early generation quinolone nalidixic acid served as an important marker for decreased susceptibility to fluoroquinolones. However, because of the emergence of newer mechanisms of fluoroquinolone resistance, some isolates may appear to be sensitive to nalidixic acid but still have decreased sensitivity to clinically important fluoroquinolones, calling into question the reliability of using nalidixic acid resistance as a marker of fluoroquinolone resistance. As a result, both the Clinical and Laboratory Standards Institute (CLSI) in the United States and European Committee on Antimicrobial Susceptibility Testing have specific fluoroquinolone breakpoints for Salmonella isolates [3-5].
CLSI guidelines consider a ciprofloxacin MIC ≤0.06 mcg/mL and levofloxacin or ofloxacin MIC ≤0.12 mcg/mL as susceptible. Typhoidal Salmonella strains with MICs above these thresholds may be associated with clinical failure or delayed response to treatment with fluoroquinolones.
In many parts of South Asia, over 80 percent of S. Typhi isolated among clinical cases are nonsusceptible to fluoroquinolones . A randomized trial in Nepal comparing ceftriaxone with gatifloxacin, a fluoroquinolone that had proven highly successful in the country just several years prior, had to be terminated early due to high rates of treatment failure in the gatifloxacin arm, which was associated with fluoroquinolone nonsusceptibility. In contrast, fluoroquinolone-nonsusceptibility appears less common in other parts of the world. In one multi-country study in Africa, fluoroquinolone nonsusceptibility was only documented in one (Kenya)  of six countries performing surveillance. More recently, fluoroquinolone resistant isolates have been reported in Nigeria . Throughout Africa, rates of fluoroquinolone nonsusceptibility in typhoidal Salmonella remain low but are rising .
Increasing rates of full resistance to fluoroquinolones have also been reported; in some cases, these resistant isolates have been classified as a subclass of the multidrug resistant (MDR) H58 typhoid strain that had widely disseminated throughout Asia and some African countries . A compilation of studies showed rates of fully quinolone-resistant organisms ranged from 0 to 13 percent, with cases reported from India, Korea, and Nepal . In a systematic review of studies from Nepal, the pooled rates of ciprofloxacin resistance increased in both S. Typhi and S. Paratyphi A, from 1.6 and 3.9 percent in 1998 to 2002 to 10.6 and 14.3 percent in 2008 to 2011 . Cases of high-level resistance to ciprofloxacin, often conferred by strains containing multiple mutations in the quinolone resistance-determining region have also been reported throughout South Asia in both S. Paratyphi and S. Typhi (MICs ≥8 mcg/mL) [13-15]. Given the rapid global spread of prior drug-resistant Salmonella strains from South Asia, there is concern that these highly resistant strains will soon appear in other parts of the world.
●Ceftriaxone resistance − In particular, ceftriaxone resistance is increasing, with reports of patients with extended-spectrum beta-lactamase-producing S. Typhi and S. Paratyphi infections [16-18]. A cluster of ceftriaxone-resistant S. Typhi infections has been linked to travel to Iraq . Multiple reports of ceftriaxone-resistant infections mediated by the acquisition of drug-resistant plasmids, such as IncX3, have been reported from India. These strains remain susceptible to azithromycin, chloramphenicol, and carbapenems [20-22].
●Azithromycin resistance − Clearly defined MIC breakpoints for azithromycin susceptibility have not been established, but data suggest that S. Typhi isolates with an MIC ≤16 mcg/mL generally respond well to azithromycin (which is concentrated intracellularly at levels 50 to 100 times greater than serum levels) and can be considered susceptible . A 15 mcg disk susceptibility zone size of ≥13 mm appears consistent with an azithromycin MIC ≤16 mcg/mL (99.7 percent sensitive).
The first report of azithromycin resistance (MIC by E-test 64 mcg/mL) in S. Paratyphi A resulting in treatment failure was reported in a traveler returning from Pakistan to Great Britain . The patient was successfully treated with a two-week course of intravenous ceftriaxone, 2 g daily. A growing number of azithromycin-resistant S. Typhi and S. Paratyphi A isolates have also been reported from South Asia, although this phenotype has not been seen in ceftriaxone-resistant organisms [25-27]. It appears to be mediated by R717Q/L mutations in the acrB gene .
Multidrug resistance — MDR strains (ie, those resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) are prevalent worldwide, though they have been in decline as other antibiotics have been more widely used for treatment of enteric fever.
MDR strains of S. Typhi and S. Paratyphi have caused numerous outbreaks in endemic regions, including South and Southeast Asia, China, and Africa [29-31]. Because of this, ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol fell out of favor as first-line agents for treatment of enteric fever.
Prevalence of MDR strains varies, throughout Africa, the Middle East, and Central Asia, from 10 to 80 percent, depending on the country [32-35]. Genome sequencing and analysis of international isolates has identified a predominant MDR S. Typhi strain, H58, that has disseminated throughout Asia and Africa, displacing more susceptible strains and driving ongoing MDR epidemics . As of 2018, approximately 75 percent of strains from Africa remain MDR, without significant change over the past 15 years .
However, some locations have reported a decrease in the prevalence of MDR strains. As an example, in a surveillance study from Kolkata, India conducted from 2009 to 2013, 18 percent of S. Typhi and no S. Paratyphi isolates were MDR . A surveillance study of isolates collected across India between 2017 and 2020 demonstrated continued declining numbers, with 2 percent of S. Typhi and no S. Paratyphi A isolates that were MDR . These patterns of resistance are reflected in travelers returning to nonendemic regions. In an analysis of over 1000 isolates submitted to the United States Centers for Disease Control and Prevention between 2008 and 2012, most of which were from infections acquired in South Asia, 13 percent of S. Typhi and no S. Paratyphi isolates were MDR strains . In a subsequent Surveillance of Enteric Fever in Asia Project study, a minority of strains from India, Nepal, and Bangladesh were MDR, while the majority of strains from Pakistan continued to show multidrug resistance .
Extensively drug-resistant typhoid — Extensively drug-resistant (XDR) strains (ie, those resistant to five antibiotics: ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, fluoroquinolones, and third-generation cephalosporins) has been described as follows:
●In 2016, a large outbreak of typhoid fever in Pakistan was caused by a strain resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins [40,41]. By the end of 2018, more than 5000 cases of this XDR S. Typhi strain were reported, with imported cases in the United Kingdom and the United States [42-44].
●In 2020, several XDR typhoid cases in individuals with no prior international travel were reported in the United States, suggesting local transmission . The strain remains susceptible to azithromycin and carbapenems, which are the main treatment options. (See 'Empiric therapy' below.)
ANTIMICROBIAL THERAPY — Enteric fever is usually treated with a single antibacterial drug. Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources. The optimal choice of drug and duration of therapy are uncertain [46-48]. The main options are fluoroquinolones, third-generation cephalosporins, and azithromycin. Carbapenems are reserved for suspected infection with extensively drug-resistant (XDR) strains. In some circumstances, older agents such as chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole may be appropriate, but these drugs are generally not used widely because of the prevalence of resistance. Oral chloramphenicol is no longer available in the United States but is still used in other parts of the world.
Empiric therapy — When treating presumptively for enteric fever or before results of susceptibility testing are available, appropriate options for empiric therapy depend, in part, on the severity of disease and the risk of infection with an antibiotic-resistant isolate.
Severe or complicated disease — For patients who have severe disease (eg, systemic toxicity, depressed consciousness, prolonged fever, organ system dysfunction, or other feature that prompts hospitalization), initial therapy with a parenteral agent is appropriate. The geographic region where infection was likely acquired helps inform the choice of parenteral agent because of the risk of resistance in certain locations:
●Infection acquired outside Pakistan or Iraq – For most patients with severe or complicated enteric fever without recent travel to Pakistan or Iraq, we suggest empiric therapy with ceftriaxone. If ceftriaxone is not available, cefotaxime is a reasonable alternative. Although some studies have demonstrated slower time to defervescence with cephalosporins (compared with fluoroquinolones), resistance to the third-generation cephalosporins is uncommon in most locations, and so ceftriaxone is likely to be an effective empiric agent in individuals without a history of travel to Pakistan or Iraq . However, if there is suspicion for ceftriaxone resistance, a carbapenem can be used while awaiting susceptibility testing  (see 'Extensively drug-resistant typhoid' above). Aztreonam has been effective in small trials and can be used for individuals who cannot take cephalosporins because of allergy [49,50]. In situations where the risk of decreased susceptibility to fluoroquinolones is low (eg, disease not acquired from South Asia or Iraq), a parenteral fluoroquinolone is also an appropriate alternative.
●Infection acquired in Pakistan or Iraq – For patients with severe or complicated enteric fever acquired in Pakistan or Iraq (eg, following recent travel to those countries), we suggest empiric therapy with a carbapenem (eg, meropenem). This is because of the presence of XDR S. Typhi in these regions. (See 'Extensively drug-resistant typhoid' above.)
Antibiotic doses and durations are listed in the table (table 1). Once symptoms improve, the patient can be transitioned to an oral agent, selected based on results of susceptibility testing, if available. Oral options and data evaluating the efficacy of antibiotic options for enteric fever are discussed elsewhere. (See 'Directed therapy' below.)
Adjunctive corticosteroid is an additional consideration for patients with severe enteric fever. (See 'Adjunctive corticosteroids for severe infection' below.)
Uncomplicated disease — Patients with uncomplicated disease have no evidence of systemic toxicity and can tolerate oral therapy. Appropriate options for empiric therapy in such patients depend on the risk of infection with an antibiotic-resistant isolate, which differs based on the geographical area where infection was acquired. (See 'Fluoroquinolone resistance' above.)
●Fluoroquinolones (ciprofloxacin or ofloxacin) are the drugs of choice for empiric therapy when infection is expected to be fluoroquinolone susceptible. This includes infection acquired in most areas of sub-Saharan Africa (except for Kenya and Nigeria). However, since fluoroquinolone resistance has emerged quickly in some areas, susceptibility testing and continued surveillance of local resistance rates is recommended to guide empiric treatment. Although fluoroquinolones are not recommended for routine use in children in the United States because of arthropathy and cartilage toxicity in exposed immature animals [51,52], clinical studies have not demonstrated sustained injury to developing bones or joints in children treated with available fluoroquinolones [53,54]. Thus, fluoroquinolone use in children is acceptable for severe infection, such as enteric fever, when alternatives are not available or appropriate.
●In contrast, for empiric oral therapy of patients with infections acquired in South Asia or other areas with a high risk of reduced susceptibility to fluoroquinolones (eg, nalidixic acid resistance), we suggest azithromycin, which achieves excellent intracellular concentrations and has established efficacy. Azithromycin is also expected to have activity against XDR isolates acquired in Pakistan. Increasing numbers of azithromycin-resistant S. Typhi have been reported from South Asia, particularly Bangladesh, so susceptibility testing should be performed. (See 'Fluoroquinolone resistance' above and 'Extensively drug-resistant typhoid' above.)
Infection with an isolate with reduced susceptibility to fluoroquinolones (see 'Fluoroquinolone resistance' above) is associated with longer time to defervescence and higher rates of treatment failure with ciprofloxacin, ofloxacin, and gatifloxacin [46,55-58]. Over a period of 10 years, fluoroquinolone effectiveness markedly declined in this setting as resistance emerged; at the same time, azithromycin remained effective and minimum inhibitory concentrations (MICs) were low and declining . Resistance to azithromycin remains rare.
However, azithromycin may be costly or unavailable in certain parts of the world, and parenteral therapy may not be necessary for many uncomplicated infections. In such cases, cefixime is another alternative, but it has some drawbacks (see 'Fluoroquinolone-nonsusceptible infection' below). If multidrug resistance is not prevalent, trimethoprim-sulfamethoxazole, amoxicillin, and chloramphenicol (if available) are potential options (see 'Multidrug resistance' above). In resource-limited settings, options may be further constrained by cost and availability.
Antibiotic doses and durations are listed in the table (table 1). If susceptibility testing demonstrates that an empirically chosen agent is active and the patient has improved, that agent can be continued as directed therapy. Data evaluating the efficacy of antibiotic options for enteric fever are discussed elsewhere. (See 'Directed therapy' below.)
Directed therapy — Ideally, definitive antimicrobial therapy for enteric fever should be based on results of susceptibility testing. S. Typhi and S. Paratyphi isolates should be directly tested for ciprofloxacin or ofloxacin sensitivity utilizing the breakpoints as described above [3,60,61]. However, such testing may be technically challenging, especially in resource-limited settings. Moreover, the diagnosis of enteric fever is often presumptive, without isolation of an organism. In cases in which susceptibility testing cannot be performed, options depend on the likelihood of antimicrobial resistance (see 'Empiric therapy' above). Infectious disease consultation is warranted for such cases if clinicians are not familiar with enteric fever and its treatment.
There are no trials demonstrating that combination antimicrobial therapy is superior to monotherapy for enteric fever. In a study of 37 individuals with nalidixic acid-resistant S. Paratyphi A bacteremia who were identified as part of an outbreak among Israeli travelers returning from Nepal, all patients improved without complications, but time to defervescence was shorter among those who were treated with ceftriaxone and azithromycin compared with ceftriaxone alone . Given the small size and observational nature of the study and the finding that all patients were infected by a single strain, additional study is needed to determine if there is any benefit of using two drugs over one. Further study evaluating combination treatment with azithromycin and cefixime versus azithromycin alone is ongoing .
Fluoroquinolone-susceptible infection — Fluoroquinolones are considered by many experts to be the drug of choice for susceptible isolates. Of the fluoroquinolones, ciprofloxacin and ofloxacin are widely available and effective. Norfloxacin is very poorly absorbed and should not be used. If a fluoroquinolone cannot be used, alternatives include azithromycin and third-generation cephalosporins. (See 'Fluoroquinolone-nonsusceptible infection' below.)
Fluoroquinolones are bactericidal, are concentrated intracellularly and in the bile, and result in rapid elimination of intracellular bacteria. They are more effective than beta-lactams against susceptible organisms. As an example, in an open-label randomized trial among patients older than 15 years, ofloxacin (200 mg orally twice daily for five days) resulted in higher cure rates compared with ceftriaxone (3 g intravenously once daily for three days) . In a separate open-label randomized trial of 82 children, resolution of fever occurred more rapidly (4.4 versus 8.5 days) with ofloxacin (10 mg/kg per day divided twice daily for five days) compared with cefixime (20 mg/kg per day divided twice daily for seven days) . There was one treatment failure in the ofloxacin group compared with 10 treatment failures and one relapse in the cefixime group.
Although fluoroquinolones are not recommended for routine use in children in the United States because of arthropathy and cartilage toxicity in exposed immature animals [51,52], clinical studies have not demonstrated sustained injury to developing bones or joints in children treated with available fluoroquinolones [53,54]. Thus, fluoroquinolone use in children is acceptable for a severe infection, such as enteric fever, when alternatives are not available or appropriate.
Fluoroquinolone-nonsusceptible infection — Fluoroquinolone nonsusceptible infections include those with reduced susceptibility to the fluoroquinolones (ie, nalidixic acid-resistant) and those with frank resistance. In infections with reduced fluoroquinolone susceptibility, treatment with ciprofloxacin or ofloxacin is associated with longer time to defervescence and higher rates of clinical treatment failure [46,66], and so should be avoided.
When fluoroquinolones cannot be used, we typically use azithromycin. If azithromycin cannot be used because of cost, availability, or other reasons, other options include third-generation cephalosporins and, if susceptibility is demonstrated, trimethoprim-sulfamethoxazole, amoxicillin, or chloramphenicol.
●Azithromycin – Azithromycin has good efficacy for enteric fever. In a systematic review that included seven randomized trials of adults and children with enteric fever, azithromycin was at least as effective as comparators (fluoroquinolones, chloramphenicol, ceftriaxone) with regards to clinical failure, time to defervescence, and relapse . For fluoroquinolone-nonsusceptible infection, azithromycin appears superior to ofloxacin. As an example, in an open-label, randomized study among Vietnamese adults and children with uncomplicated typhoid fever due to nalidixic acid-resistant or multidrug-resistant isolates, azithromycin (1 g daily for five days) resulted in a trend towards greater clinical cure rates (82 versus 64 percent), faster time to defervescence (mean 5.8 versus 8.2 days) and lower rates of post-treatment fecal carriage (1.6 versus 19 percent) . Early convalescent fecal shedding may spread the organism in a community even if few of these individuals become chronic carriers.
●Cephalosporins – Third-generation cephalosporins also have demonstrated efficacy but require a longer duration of therapy. Although the optimal duration has not been established, at least 10 to 14 days are warranted because of the risk of relapse with shorter durations [49,69-71]. In two randomized trials, seven days of ceftriaxone (50 to 75 mg/kg per day) resulted in relapse within four weeks in 14 percent of children [69,70]. In one of these studies, children were assigned to seven days of therapy with either azithromycin (10 mg/kg per day; maximum 500 mg) or ceftriaxone (75 mg/kg per day; maximum 2.5 g per day) . There were four relapses with ceftriaxone compared with none with azithromycin (14 versus 0 percent).
Among the third-generation cephalosporins, ceftriaxone may be superior to cefotaxime . Oral cefixime has not been extensively compared directly with ceftriaxone, but appears to be of generally comparable efficacy [49,71]. Cefixime for 14 days was comparable to azithromycin given for 7 days (93 versus 87 percent cure) in a study of children with uncomplicated enteric fever in Bangladesh . However, other studies have reported a slower time to defervescence and a relatively high rate of on-treatment failure with cefixime compared with other agents [65,74].
Although gatifloxacin had previously been proposed as an option for isolates with reduced susceptibility to fluoroquinolones (ie, nalidixic acid-resistant isolates) because it appeared to retain relatively good activity against them [75-77], the emergence of frankly fluoroquinolone-resistant isolates has limited its utility. Moreover, it is not widely available, having been withdrawn from most countries because of associated dysglycemia.
The rise and fall of gatifloxacin as an effective therapy for typhoid has been demonstrated in several trials from Nepal. In an analysis of four trials conducted between 2005 and 2014, gatifloxacin had equivalent or better fever clearance times in the first three trials when compared with cefixime, chloramphenicol, and ofloxacin . However, during the course of the trials, MICs to fluoroquinolones steadily rose, and these higher MICs were associated with slower time to defervescence with gatifloxacin. In the fourth randomized trial, which was conducted from 2011 to 2014 and included children and adults with documented or suspected enteric fever, treatment failure was similar with gatifloxacin versus ceftriaxone, each given for seven days (15 and 16 percent, respectively) . However, among those with culture-confirmed S. Typhi infection, 25 percent had fluoroquinolone-resistant isolates, and failure was greater with gatifloxacin (26 versus 7 percent). The trial was stopped early because of the high rates of fluoroquinolone resistance identified. Fluoroquinolones are therefore no longer considered appropriate empiric therapy for enteric fever in this region.
OTHER TREATMENT CONSIDERATIONS
Adjunctive corticosteroids for severe infection — For patients with suspected or known enteric fever and severe systemic illness (delirium, obtundation, stupor, coma, or shock), we suggest adjunctive dexamethasone (3 mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours).
In a randomized, prospective, double-blind study performed in Indonesia in the early 1980s among 38 adults and children with severe enteric fever (shock or obtundation), the addition of high-dose dexamethasone to chloramphenicol treatment reduced mortality compared with chloramphenicol alone (10 versus 55 percent) . Adjunctive corticosteroids did not increase the rate of other complications, carriage, or relapse. Subsequent observational studies have also supported the benefit [79,80], but whether the adjunctive dexamethasone is beneficial with other antibiotics or in different clinical settings remains uncertain.
Patients with ileal perforation — For patients with ileal perforation, prompt surgical intervention is usually indicated, as is broader antimicrobial coverage to cover peritonitis and potential secondary bacteremia with enteric organisms (see "Antimicrobial approach to intra-abdominal infections in adults"). The extent of surgical intervention remains controversial; the best surgical procedure appears to be segmental resection of the involved intestine, when possible [81,82].
In a retrospective review from West Africa including 112 patients undergoing laparotomy for typhoid perforation, most of the perforations were single (77 percent) and in the terminal ileum . Primary repair was successful in 84 percent of cases, although reoperative management was required in some patients who did not respond immediately. Even with surgery, mortality rates of 14, 16, and 34 percent have been reported in series from Nigeria, Togo, and the Ivory Coast, respectively [83-85].
FOLLOW-UP — Successful treatment in uncomplicated cases usually results in clinical improvement within three to five days. In most clinical trials, the mean time to defervescence is four to six days, so persistent fevers of this duration following treatment initiation does not imply therapeutic failure. Patients should be subsequently monitored for or instructed to report recurrent symptoms, which could reflect relapse.
Relapse — Relapse of enteric fever after clinical cure can occur in immunocompetent individuals; in such cases, it typically occurs two to three weeks after resolution of fever. The risk of relapse depends on the antibiotic used to treat the initial infection. Relapse rates with chloramphenicol, a bacteriostatic agent, were 10 to 25 percent, but subsequent studies that have included multidrug-resistant S. Typhi infections and newer antibiotics have noted lower relapse rates of 1 to 6 percent [49,65,76].
Relapsed infection should be treated with an additional course of antibiotics, guided by susceptibility testing. Usually, the isolate has the same susceptibility pattern as the initial infection. A longer treatment course with a third-generation cephalosporin is also reasonable.
Post-acute shedding and chronic carriage
●Indication for evaluation – Evaluation for S. Typhi (or S. Paratyphi A) post-acute shedding or carriage is warranted for individuals at increased risk for transmission to others; these include food handlers, healthcare workers, childcare workers, and children in daycare. Specific policies on who should be screened vary by local health ordinances. Some states in the United States, for example, require screening follow acute typhoid illness for all individuals and their contacts, while other states only require screening for high-risk groups.
●Post-acute stool shedding
•Definition and risk factors – Surveillance studies of patients with acute typhoid fever have shown that up to 10 percent of untreated individuals shed bacteria in their stool up to three months post-infection . With antibiotic treatment, approximately 5 percent of children continue to shed S. Typhi 30 days after onset of fever [86,87].
•Screening approach – To document clearance of post-acute stool shedding, samples are typically collected at least one week after discontinuation of antibiotics and at least one month after illness onset. Typically, three stool (with or without urine) samples are collected at least 24 hours apart. If any cultures are positive, repeat cultures should be performed monthly until there are three consecutive negative samples.
•Definition and risk factors – Chronic carriage of Salmonellae is defined as excretion of the organism in stool for more than 12 months after the acute infection. Chronic carriage rates after S. Typhi infection range from 1 to 6 percent . Risk factors include older age (>50 years), female sex, gallbladder abnormalities, and gallstones [89,90]. Risk factors for chronic urinary carriage include kidney stones and schistosomal infection . (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'Salmonella'.)
•Screening approach – At least three stool samples should be collected, separated by at least 24 hours; the estimated sensitivity is 70 to 80 percent . Serologic screening is not recommended for identifying chronic carriers; some studies have identified high levels of anti-Vi or anti-YncE antibodies in chronic carriers, though specificity appears to vary by setting.
-Clinical approach – Management of chronic carriage generally consists of antimicrobial therapy. If eradication is not achieved with antimicrobial therapy, cholecystectomy may be warranted. The effectiveness of cholecystectomy in eradicating carriage is around 70 to 80 percent. The efficacy may be better with combined antibiotic and surgical management; however, available data are decades old [92,93].
-Antibiotic selection – For patients with a fluoroquinolone-susceptible isolate, treatment with ciprofloxacin (500 to 750 mg orally twice daily) or levofloxacin (500 mg orally once daily) for four weeks is reasonable. Four weeks after completion of therapy, we obtain at least three stool samples for culture .
For patients with a fluoroquinolone-nonsusceptible isolate, treatment should be guided by susceptibility data; possible regimens include high-dose amoxicillin (eg, 75 to 100 mg/kg per day) for six weeks or trimethoprim-sulfamethoxazole (160 mg/800 mg orally twice daily) for three months [95-99].
This approach is supported by a 2022 systematic review including 8 studies and 126 patients with enteric fever treated with fluoroquinolones or beta-lactams (amoxicillin or ampicillin); successful eradication was achieved more frequently with fluoroquinolones (92 versus 68 percent) . However, only one study was randomized and blinded, and the other studies included no control group; in addition, the trials were done prior to widespread antimicrobial resistance.
OUTCOMES — Effective antibiotic therapy has dramatically impacted the outcomes of enteric fever. In the pre-antibiotic era, mortality rates were 15 percent or greater [101,102] and survivors experienced a prolonged illness lasting weeks, with months of subsequent debilitation. Approximately 10 percent of untreated patients relapsed and up to 4 percent become chronic carriers of the organism.
Among those receiving medical care in the post-antibiotic era, the average mortality rate from enteric fever is estimated to be less than 1 percent . Although a 2018 systematic review reported a higher case-fatality rate, it was likely an overestimate of contemporary mortality rates, as high rates were seen primarily in older or smaller studies . Mortality rates from more recent studies are low. As an example, in a study of nearly 3000 individuals receiving care for culture-confirmed enteric fever in Pakistan from 2012 to 2014, there were no deaths reported . In the United States, a Centers for Disease Control and Prevention compilation of 10 hospital-based typhoid fever series reported a mean case-fatality rate of 2 percent (range 0 to 14.8 percent), but noted that these series capture only the most severe and hospitalized cases in those with access to care .
Food and water safety — Enteric fever results from the ingestion of contaminated food or water. The inoculum in food is likely higher than that in contaminated water. Access to fresh water, prioritization of sanitation and hygiene, and education about food and water safety are essential preventive strategies.
For travelers, the main mechanism of transmission is ingestion of the local cuisine or water in areas where sanitation and personal hygiene may be poor. Travelers should be advised on behavioral precautions. (See "Travel advice", section on 'Food and water'.)
In endemic areas — The World Health Organization (WHO) recommends implementation of national typhoid vaccination programs as part of broader control efforts in settings where typhoid is endemic. Of available vaccines, it prefers typhoid conjugate vaccines for their efficacy and established safety in infants and young children, as well as their greater and more durable immunogenicity compared with other vaccines . It recommends administration of typhoid conjugate vaccine for infants and children six months of age or older, with catch-up vaccination campaigns, if possible, for children up to 15 years old. (See 'Licensed vaccines' below.)
In nonendemic areas — Typhoid vaccination is indicated in travelers to endemic areas and other individuals with risk for exposure, but available vaccines are not entirely protective. Specific indications and vaccine options vary by country.
In the United States, typhoid vaccination is recommended for travelers (even short-term travelers) to areas where there is risk of exposure to S. Typhi, for individuals with intimate exposure to a documented S. Typhi chronic carrier (eg, household contacts), and for individuals whose work exposes them to cultures or specimens containing S. Typhi (eg, laboratory workers) . Typhoid conjugate vaccine is not yet available in the United States. Either the polysaccharide or oral vaccine formulation is appropriate, although the oral vaccine should be avoided in immunocompromised and pregnant individuals since it is a live vaccine. If repeated exposure to S. Typhi is expected, repeat typhoid vaccination is advised to maintain immunity. (See "Immunizations for travel", section on 'Typhoid vaccine'.)
Vaccination is appropriate even in those who have a history of enteric fever, particularly in those not living in endemic areas, if re-exposure is expected. Natural infection does not provide complete protection against recurrent illness (which is not the same as relapsed infection). One study suggests early treatment of natural infection may blunt humoral responses to capsular antigens . The optimal timing for vaccination following clinical illness is not known.
Licensed vaccines — Several typhoid vaccines have been licensed, although they are not all universally available. None are completely effective against S. Typhi and none have been demonstrated to provide protection against paratyphoid fever caused by S. Paratyphi A.
●Vi typhoid conjugate vaccines (TCV) – These vaccines consist of the Vi polysaccharide antigen linked to various carrier proteins. Typbar-TCV, a Vi-TT (tetanus toxoid) conjugate, is the representative vaccine of this type; it is administered as a single intramuscular dose. The need for revaccination for continued protection is uncertain. It is licensed in India, Nepal, and several other countries, but it is not yet available in Europe or the United States. A second typhoid conjugate vaccine (Typhibev), containing Vi conjugated to CRM197, a nontoxic mutant of diphtheria toxin, was prequalified in December 2020. This vaccine demonstrated safety and noninferior immunogenicity in clinical trials  but has not yet been evaluated for clinical efficacy. A Vi-DT (diphtheria toxin) vaccine was found to have noninferior immunogenicity in a Phase 3 trial in Nepal . Two other Vi-TT conjugate typhoid vaccines (PedaTyph and ZyVac-TCV) are available in India .
Emerging evidence suggests good efficacy of TCVs. In several randomized trials from Nepal, Bangladesh, and Malawi, which together included over 100,000 children, vaccine efficacy of Typbar-TCV against culture-confirmed typhoid fever ranged from 81 to 85 percent compared with control vaccines [112-114]. As an example, in the trial from Nepal, among over 20,000 children aged 9 months to 16 years, the incidence of typhoid fever over the year following Typbar-TCV vaccination was 79 cases compared with 428 cases per 100,000 person-years after meningococcal conjugate vaccination (vaccine efficacy 82 percent, 95% CI 59-92) . Typbar-TCV was 97 percent (95% CI 95-98) effective against extensively drug-resistant (XDR) S. Typhi . No major vaccine-associated adverse events were identified in any of the trials.
Conjugate vaccines appear to be more immunogenic and better at inducing long-term memory responses compared with other typhoid vaccines [116-118]. In a randomized trial of individuals aged 2 to 45 years in India, the conjugate vaccine (Typbar-TCV) resulted in higher seroconversion rates and higher antibody titers after three to five years than the polysaccharide vaccine, especially in young children . It was also safe and immunogenic in a parallel open-label trial of children aged 6 to 23 months, with anti-Vi IgG antibodies persisting up to five years in approximately 85 percent.
●Vi polysaccharide vaccine – This consists of the Vi polysaccharide antigen. It is administered as a single intramuscular dose. It can also be given subcutaneously. If continued protection is needed, revaccination is recommended every two to three years.
In a systematic review and meta-analysis of randomized controlled trials, efficacy at one, two, and three years was 69, 59, and 55 percent .
●Ty21a vaccine – This is a live oral vaccine that consists of an attenuated S. Typhi strain Ty21a. It is administered in three to four doses taken on alternate days. If continued protection is needed, revaccination is recommended every three to five years.
In a systematic review and meta-analysis of randomized controlled trials, efficacy at one, two, and three years was 45, 59, and 56 percent . There is some evidence that the Ty21a vaccine may confer partial protection against S. Paratyphi B .
Adverse effects associated with these vaccines are generally mild (eg, fever or injection site pain or swelling) [112,117,120].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Acute diarrhea in children" and "Society guideline links: Travel medicine".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Enteric (typhoid and paratyphoid) fever (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Antimicrobial resistance – Treatment of enteric fever has been complicated by the development of antimicrobial resistance. In particular, resistance to clinically important fluoroquinolones has become a major problem worldwide, particularly in Asia. Most Salmonella Typhi and Salmonella Paratyphi isolates remain susceptible to azithromycin and third-generation cephalosporins. However, an extensively drug-resistant (XDR) isolate has emerged in Pakistan that is resistant to many agents, including third-generation cephalosporins and fluoroquinolones. (See 'Antimicrobial resistance' above.)
●Antibiotic selection – Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources (table 1). (See 'Antimicrobial therapy' above.)
•Severe or complicated disease – Patients with severe disease (systemic toxicity, depressed consciousness, prolonged fever, organ system dysfunction, or other feature that prompts hospitalization) should be treated initially with a parenteral antibiotic. For such patients, who have acquired infection outside of Pakistan or Iraq, we suggest ceftriaxone (Grade 2B). Alternatives include cefotaxime or, if the risk of decreased susceptibility to fluoroquinolones is low (eg, disease not acquired from South Asia or Iraq), a parenteral fluoroquinolone.
If there is suspicion for ceftriaxone resistance, a carbapenem can be used while awaiting susceptibility testing. For patients with severe typhoid fever acquired in Pakistan or Iraq, we suggest empiric therapy with a carbapenem (eg, meropenem) because of the risk of ceftriaxone-resistant and XDR typhoid (Grade 2C). (See 'Severe or complicated disease' above.)
•Uncomplicated disease – For patients with uncomplicated enteric fever, antibiotic selection depends on the likelihood of reduced susceptibility to fluoroquinolones, which is highest in infections acquired in South Asia. In the absence of known or suspected reduced fluoroquinolone susceptibility, we suggest antibiotic therapy with ciprofloxacin (Grade 2B).
For patients with uncomplicated enteric fever due to an isolate known or suspected to have reduced fluoroquinolone susceptibility (including patients with infection acquired in Pakistan), we suggest azithromycin (Grade 2B). Ceftriaxone is an alternative (except for patients with infection acquired in Pakistan or Iraq). With increasing reports of azithromycin-resistant S. Typhi from South Asia, susceptibility testing should be performed. (See 'Uncomplicated disease' above.)
•Directed therapy – Empiric antibiotic regimens can be adjusted if and when formal sensitivities are available. (See 'Directed therapy' above.)
●Adjunctive corticosteroids for severe infection – For patients with suspected or known enteric fever and severe systemic illness (delirium, obtundation, stupor, coma, or shock), we suggest adjunctive dexamethasone (3 mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours) (Grade 2B). (See 'Adjunctive corticosteroids for severe infection' above.)
●Patients with ileal perforation – Treatment of ileal perforation warrants surgical therapy in addition to antibiotic therapy to cover both enteric fever and enteric organisms. (See 'Patients with ileal perforation' above.)
●Relapse – Successful treatment in uncomplicated cases usually results in clinical improvement within three to five days, with fever clearance at four to six days. Relapse of enteric fever after clinical cure can occur two to three weeks after resolution of illness and should be treated with an additional course of antibiotics, guided by susceptibility testing. (See 'Relapse' above.)
●Chronic carriage – Chronic Salmonella carriage is defined as excretion of the organism in stool >12 months after acute infection. (See 'Post-acute shedding and chronic carriage' above.)
•Indication for evaluation – Evaluation for post-acute S. Typhi shedding or carriage is warranted for individuals at increased risk for transmission to others; these include food handlers, health care workers, children in daycare, and childcare workers.
•Management – For chronic Salmonella carriers who are at increased risk for transmission to others (such as food handlers, health care workers, and childcare workers), we suggest antibiotic treatment (Grade 2C); for those with fluoroquinolone-susceptible isolates, we suggest treatment with ciprofloxacin (Grade 2C).
•Food and water safety – Enteric fever results from the ingestion of contaminated food or water; attention to food safety is important for travelers to regions where sanitation and personal hygiene may be poor. (See 'Food and water safety' above.)
•Vaccination – (see 'Vaccination' above):
-Three vaccines are available globally for protection against S. Typhi: parenteral Vi polysaccharide vaccine, live oral S. Typhi vaccine strain Ty21a, and parenteral Vi conjugate vaccine. None of these vaccines offer complete protection, and periodic revaccination is needed if exposure risk continues.
-In endemic areas, the World Health Organization (WHO) recommends implementation of national typhoid vaccination programs, preferably with a conjugate typhoid vaccine, as part of broader control efforts. The conjugate vaccine is not available in the United States or Europe.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Elizabeth L. Hohmann, MD, and Edward T Ryan, MD, DTMH, who contributed to an earlier version of this topic review.
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