• Typhoid fever typically manifests as an undifferentiated acute febrile illness.
• Soft splenomegaly, normal or low white cell count, and elevated liver enzymes are subtle diagnostic pointers.
• Blood culture, drawn before antibiotic administration, is the most useful investigation.
• Consider presumptive treatment in appropriate epidemiologic settings.
• Decreased susceptibility to fluoroquinolones is widespread among
Salmonella enterica serovar Typhi.
• High-dose fluoroquinolones are suboptimal for treating such infections.
• Azithromycin (Zithromax)1 is the preferred drug for uncomplicated typhoid fever.
• Ceftriaxone (Rocephin)1 is preferred for treating hospitalized and seriously ill patients.
1 Not FDA approved for this indication.
Typhoid fever is a bacteremic infection caused by the gram-negative bacillus Salmonella enterica serovar Typhi. S. Paratyphi also causes an illness clinically indistinguishable from typhoid fever. Humans are the only known host of S. Typhi, and it is transmitted by ingestion of contaminated food or water. Improvement in sanitation and hygiene led to the elimination of typhoid fever from the developed world long before the advent of antibiotics. On the other hand, in parts of the world lacking sanitation, it continues to be an important cause of febrile illness despite the availability of effective antibiotics.
Typhoid fever is endemic in the developing world, especially the South and South East Asian countries of India, Nepal, Pakistan, Bangladesh, Vietnam, and Indonesia. Annual incidence in endemic settings is typically more than 100 cases per 100,000 population, and it predominantly affects children and young adults. Apart from sick persons with typhoid fever, convalescent carriers and asymptomatically infected food handlers (long-term carriers) are the sources of infection. Potential vehicles of infection include food or water consumed from roadside eateries, ice cubes and ice cream made from contaminated water, and raw vegetables and fruits. In contrast, most cases of typhoid fever in developed countries are imported by travel, especially to the Indian subcontinent.
Pathogenesis and Clinical Features
Following ingestion, the bacilli invade and multiply in the small- intestinal lymphoid tissue before entering the bloodstream. This primary bacteremia leads to widespread seeding of the reticuloendothelial system and intestinal lymphoid tissue, where the infection is amplified and spills over into the circulation. Onset of symptoms usually coincides with this secondary bacteremia.
Interestingly, unlike other Gram-negative bacteremic infections, septic shock develops relatively late in the course of illness, and the infection can be eminently cured by oral antibiotic therapy. Nonetheless, it should be emphasized that any delay in initiating antibiotic therapy increases the risk of complications (Box 1).
|Complications of Typhoid Fever|
Symptomatic liver dysfunction
Osteomyelitis and soft tissue abscesses
Multiorgan dysfunction syndrome
During the first week, temperature gradually increases in a stepladder fashion. Localizing symptoms are usually minimal. Anorexia, lassitude, and malaise are often marked. Headache and vomiting are common; however, a supple neck helps rule out meningitis. Abdominal symptoms such as constipation, loose stools, and abdominal pain are not infrequent, but they are nonspecific and often overlooked. Soft, tender enlargement of liver or spleen is seen in about half the patients. Rose spots and relative bradycardia, though classic, are rare. When the infection goes untreated, hypertrophied lymphoid tissue of the Peyer’s patches can ulcerate toward the end of the second week, resulting in torrential gastrointestinal bleeding, small intestinal perforation, and secondary bacterial peritonitis.
Patients with severe illness can present with a muttering delirium described as coma vigil. Untreated typhoid fever often resolves spontaneously in about 4 to 6 weeks. However, the risk of death is high (>10%), and relapses are frequent. Many patients excrete S. Typhi in feces and urine during convalescence (convalescent carriers), and some of them continue to excrete beyond 1 year (long-term carriers).
Current Pattern of Antimicrobial Susceptibility
Since 1990, a sea change has occurred in the antimicrobial susceptibility of S. Typhi in endemic countries and elsewhere. Unregulated use of fluoroquinolones has resulted in emergence of S. Typhi strains with decreased susceptibility. These strains have a subthreshold increase in minimal inhibitory concentration (MIC) that is not detected by conventional disk-diffusion testing. Hence, determination of MIC is recommended at present. Resistance to nalidixic acid (NegGram) (a quinolone) is often used as a surrogate marker for such strains. In fact, most infections in the community are now caused by nalidixic acid-resistant S. Typhi (NARST). Not surprisingly, this change is reflected in far-away geographic locales such as the United States and the United Kingdom.
Clinical features are nonspecific, and laboratory testing is essential to confirm a diagnosis of typhoid fever. A soft splenomegaly, absence of leukocytosis, mild leukopenia, and modest elevation of transaminases are subtle pointers to a diagnosis of typhoid fever. Blood culture drawn early in the illness before initiation of antibiotics is often fruitful and is the gold standard for the diagnosis of typhoid fever.
The time-honored Widal test, which detects agglutinating antibodies to somatic and flagellar antigens of S. Typhi, adds little to decision making. Initial enthusiasm about rapid serologic tests such as Typhidot and Tubex TF has not been confirmed in community-based studies. None of these tests are sensitive enough to rule out typhoid. In a patient who has nonlocalizing acute febrile illness lasting more than 5 to 7 days in a suggestive epidemiologic setting (residence in or travel to endemic area; outbreaks), it is prudent to treat presumptively for typhoid fever, after reasonably ruling out competing diagnoses such as malaria, dengue, leptospirosis, and rickettsial infection.
Fluoroquinolones (ciprofloxacin [Cipro] or ofloxacin [Floxin]1 7.5 mg/kg twice a day for 5–7 days) are unparalleled in efficacy for treating fully susceptible S. Typhi strains. However, their use is associated with frequent treatment failures, prolonged defervescence, and higher rates of complications in NARST infections. Given the widespread emergence of NARST, fluoroquinolones are no longer to be considered the drug of choice. Several alternatives have been evaluated in randomized, controlled trials for treating uncomplicated typhoid fever caused by NARST (Table 1). Ease of oral administration, proven efficacy, and safety (under FDA review) make azithromycin (Zithromax)1 a reasonable first choice for uncomplicated typhoid fever. In hospitalized seriously ill patients and treatment failures, parenteral ceftriaxone (Rocephin)1 is preferred. Usually, it takes about 4 to 7 days for defervescence after the initiation of antibiotics.
Antipyretics should be used for symptom relief; ibuprofen (Motrin; 10 mg/kg every 6 hours) is superior to acetaminophen (Tylenol; 12 mg/kg every 6 hours). However, ibuprofen should be avoided when dengue fever is a possibility. A soft, low-residue diet is traditionally advised to prevent intestinal perforation. Such a practice, however, is not founded on scientific evidence. Treatment of S. Paratyphi infection is identical to that of S. Typhi infection.
Outcomes of Alternative Treatments for Nalidixic Acid–Resistant S. Typhi (NARST) Infection Evaluated in Randomized, Controlled Trials
Data from Arjyal A, Basnyat B, Nhan HT, et al: Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial. Lancet Infect Dis 2016;16:535. Dolecek C, Tran TP, Nguyen NR, et al: A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One 2008;3:e2188; Pandit A, Arjyal A, Day JN, et al: An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS One 2007;2:e542; and Parry CM, Ho VA, Phuong le T, et al: Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother 2007;51:819.
1 Not FDA approved for this indication.
2 Not available in the United States.
3 Exceeds dosage recommended by the manufacturer.
Sustained improvement in sanitation and access to safe drinking water are essential to control typhoid fever in endemic areas.
Avoiding potentially contaminated food and beverages and being vaccinated before travel decrease the risk of typhoid fever among travelers (see the article on travel medicine). Recently, mass administration of the Vi polysaccharide vaccine (Typhim Vi, Typherix [outside United States]) has been found to confer herd immunity and is a potential tool for the control of typhoid fever in endemic settings.
1. Arjyal A., Basnyat B., Nhan H.T., et al. Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open- label, two-centre, randomised controlled trial. Lancet Infect Dis. 2016;16:535.
2. Date K.A., Newton A.E., Medalla F., et al. Changing patterns in enteric fever incidence and increasing antibiotic resistance of enteric fever isolates in the United States, 2008-2012. Clin Infect Dis. 2016;63:322.
3. Dolecek C., Tran T.P., Nguyen N.R., et al. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS ONE. 2008;3:e2188.
4. Effa E.E., Bukirwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. (4):2008 CD006083.
5. Karki S., Shakya P., Cheng A.C., et al. Trends of etiology and drug resistance in enteric fever in the last two decades in Nepal: a systematic review and meta-analysis. Clin Infect Dis. 2013;57:e167.
6. Pandit A., Arjyal A., Day J.N., et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS ONE. 2007;2:e542.
7. Parry C.M., Ho V.A., Phuong le T., et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin- azithromycin combination for treatment of multidrug- resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother. 2007;51:819.
8. Thriemer K., Ley B., Menten J., et al. A systematic review and meta-analysis of the performance of two point of care typhoid fever tests, Tubex TF and Typhidot, in endemic countries. PLoS One. 2013;8:e81263.
9. Vinh H., Parry C.M., Hanh V.T., et al. Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of uncomplicated typhoid fever. Pediatr Infect Dis J. 2004;23:226.
10. Wain J., Hendriksen R.S., Mikoleit M.L., et al. Typhoid fever. Lancet. 2015;385:1136.
1 Not FDA approved for this indication.