AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Typhoid fever is a bacterial illness caused by Salmonella typhi, also known as Salmonella enterica serotype Typhi, a gram-negative rod found only in humans. This illness is characterized by persistent fever, abdominal pain, severe anorexia, constipation or mild diarrhea, and delirium. Most cases in the United States are acquired abroad and involve children, adolescents, and young adults. A similar, but less severe, disease is caused by Salmonella paratyphi A. Ocular manifestations are rare in typhoid fever.

Pathophysiology

Following ingestion of an infectious dose of at least 10,000 bacteria, mucosal penetration occurs in the distal ileum resulting in a transient, asymptomatic bacteremia. The organisms survive and multiply within mononuclear phagocytes located in lymph nodes, spleen, liver, and bone marrow.

The clinical phase of the disease begins within 1-3 weeks, resulting from persistent bacteremia. Hematogenous spread to ileal Peyer patches and the gall bladder reintroduces bacteria to the gut lumen and stool cultures again become positive, allowing continued fecal-oral spread of the disease. Mucosal ulceration overlying hyperplastic Peyer patches in the ileocecal region may result in pain, diarrhea, bleeding, and occasional perforation.

Frequency

United States

Approximately 500 cases of typhoid fever are reported annually in the United States. More than two thirds of those cases are contracted during travel abroad, most commonly to the Indian subcontinent. Most cases acquired in the United States are the result of local outbreaks or occur in patients with underlying medical disease. For example, the rate among patients with HIV is 60 times greater than the general population. The risk for travelers is less than 1 case in 10,000 trips, but this risk increases to 4 cases in 10,000 trips to high-risk countries.

International

According to the World Health Organization 2004 census, approximately 21.6 million cases occur per year worldwide, mostly in Asia, Africa, and Latin America, with 200,000 fatalities. Global incidence is about 0.5%, but incidence rates as high as 2% have been reported in hot spots, such as Indonesia and Papua New Guinea, where typhoid fever ranks among the 5 most common causes of death. In these countries, 91% of cases involve children aged 3-19 years, and 20,000 deaths occur per year.

Mortality/Morbidity

• The introduction of chloramphenicol reduced the case fatality rate from 12% to 4%, although this figure remains over 10% in the developing world despite antibiotic availability. Altered mental status has been associated with a high case-fatality rate.
• Most symptoms resolve without antibiotics within 3 weeks of onset in the majority of patients. Rare fatal complications include intestinal perforation or severe hemorrhage. Localized infections such as cholangitis, urinary tract infection, pneumonia, osteomyelitis, arthritis, meningitis, and endophthalmitis occasionally are seen. Spontaneous splenic rupture and multiple brain abscesses also have been reported.
• Relapse occurs in as many as 10% of patients, while 1-3% of patients become long-term carriers following recovery.

Race

No reported racial predilection exists.

Sex

Both genders appear equally susceptible.

Age

Typhoid fever affects adults and children of all ages.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• US travelers abroad have about a 1 in 10,000 risk of contracting typhoid fever, but this risk increases several fold when visiting countries with endemic typhoid.
• Symptoms develop gradually in most cases with maximal severity occurring during the second or third week following exposure.
• Constitutional symptoms include fever, chills, headache, sore throat, muscle pain, and weakness.
• Many patients complain of a skin rash and cervical adenopathy.
• Gastrointestinal symptoms include nausea, vomiting, anorexia, diarrhea, constipation, and abdominal pain.
• Neurologic symptoms include altered mental status and occasional seizures.
• Patients with ocular manifestations generally complain of pain and decreased vision.
• Recovery is characterized by diminishing fever and begins by the fourth week in patients without antibiotic treatment. In contrast, antibiotic use usually results in defervescence in less than 7 days.

Physical

• Relative bradycardia (less tachycardia than expected for the degree of fever) may occur in up to 50% of patients but is not a reliable diagnostic indicator.
• Faintly erythematous maculopapules or rose spots occur on the trunk and may become hemorrhagic.
• Cervical adenopathy and hepatosplenomegaly are often present.
• Intestinal bleeding may occur from ulceration of mucosa overlying hyperplastic ileal Peyer patches.
• Altered mental status and seizures may occur.
• Ocular manifestations are rare and occur in association with systemic illness.
• • These manifestations may include lid abscesses, corneal ulcers, uveitis, vitreous hemorrhage, retinal hemorrhage or detachment, optic neuritis, extraocular muscle palsies, orbital thromboses, and orbital abscesses.
  • Most of the ocular complications probably result from direct invasion by the organism into ocular tissues.

Causes

• Typhoid fever is most prevalent in developing countries where sanitary water and sewage systems are lacking. Transmission occurs most often by one of the following mechanisms:
• • Ingestion of contaminated food or water
  • Contact with an acute case of typhoid fever
  • Contact with a chronic asymptomatic carrier
• Other diagnostic considerations
• The differential diagnosis of infectious diseases depends on whether the patient has been traveling recently outside the United States.
• Involvement of a specialist in infectious disease is strongly encouraged. In addition, noninfectious cases of febrile illness, such as lymphoma, also should be considered.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• New diagnostic tests include those for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies, with rapid results (2 minutes to 3 hours). The Typhidot-M test has a specificity of 75% and a sensitivity of 95%. The Tubex test is rapid and detects the O9 antigen.
• The classic Widal test is rarely used because of its low sensitivity and specificity.
• Blood, urine, and stool cultures are still frequently used to isolate S typhi, but the yield is only about 70%. The duodenal string test may be used to culture bile.
• CBC may reveal anemia and thrombocytopenia.
• Liver function test results are commonly elevated.
• Renal dysfunction may occur, but chronic renal failure has not been reported.

Imaging Studies

• Abdominal radiographs demonstrate free air in cases of intestinal perforation.

Procedures

• Bone marrow biopsy results are positive in as many as 90% of individuals who are affected; therefore, performing a bone marrow biopsy is useful in cases of diagnostic uncertainty.

Histologic Findings

S typhi is a motile, gram-negative bacillus.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Chloramphenicol was the initial drug of choice (DOC) but is not commonly used because of widespread resistance, high relapse rates, and risk of bone marrow toxicity.
• The current DOC for adults is an oral fluoroquinolone, most commonly oral ciprofloxacin. This drug combines a lower documented resistance rate with excellent penetration into macrophages and the biliary system, which may reduce relapse rates and chronic carrier states. Alternative antibiotics can be used if sensitivities are known or suspected resistance is low. However, there has been a sharp increase in strains resistant to fluoroquinolones, trimethoprim/sulfamethoxazole, and ampicillin.
• The current DOC for children and pregnant women is parenteral ceftriaxone.
• Patients in shock or with altered mental status may benefit from parenteral corticosteroid administration.
• Supportive care often is required, including intravenous fluids and occasionally transfusion. The use of antipyretics has been discouraged due to risk of shock, but a recent study of 29 children demonstrated no complications with acetaminophen or ibuprofen.
• Nearly all ophthalmic complications are managed medically, including infection, uveitis, serous retinal detachment, and other presumed sequelae of inflammation.

Surgical Care

• Prompt surgical intervention for severe intestinal bleeding or bowel perforation has been shown to reduce mortality substantially.
• A role may exist for cholecystectomy in treatment of the long-term carrier state with underlying biliary disease.
• Surgical drainage of lid or orbital abscesses occasionally is required. Postoperative topical antibiotic coverage should contain chloramphenicol 1% or ciprofloxacin 0.3%, the only ophthalmic ointments with activity against S typhi.

Consultations

Infectious disease, general surgery, and gastroenterology

Diet

Initially nothing by mouth (NPO), advance as tolerated

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other antibiotics in addition to those listed as DOC depend on assessment of resistance risk and/or known sensitivities. These include trimethoprim-sulfamethoxazole, ampicillin, amoxicillin, azithromycin, and third-generation cephalosporins. Chloramphenicol ophthalmic is useful topically but no longer recommended as systemic therapy due to widespread resistance, recurrence risk, and bone marrow toxicity.

Drug Category: Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.

Drug Name	Ceftriaxone (Rocephin)
Description	DOC for children and pregnant women.
Adult Dose	1-2 g IV qd for 5-7 d
Pediatric Dose	50-80 mg/kg IM qd for 5-7 d
Contraindications	Absolute: Cephalosporin hypersensitivity Relative: Breastfeeding; coagulopathy; colitis; GI disease; penicillin hypersensitivity
Interactions	Aminoglycosides, loop diuretics, macrolides, tetracycline, others
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause nonspecific GI complaints, eosinophilia, leukopenia, rash, urticaria, and seizures; bacterial overgrowth of nonsusceptible organisms can result from prolonged use

Drug Name	Ciprofloxacin ophthalmic (Ciloxan)
Description	Inhibits bacterial growth by inhibiting DNA gyrase. Available as 0.3% solution or ointment.
Adult Dose	Apply 1 gtt or 1-cm ribbon to inferior cul-de-sac of affected eye(s); frequency of topical use is dictated by clinical setting
Pediatric Dose	<2 years: Not established (ointment) >2 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	A white crystalline precipitate located in superficial portion of corneal defect may occur (onset starts in 1-7 d); precipitate usually is cleared within 2 wk and does not adversely affect clinical course or outcome; do not use in ocular infections that may become systemic; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Chloramphenicol ophthalmic (AK-Chlor, Chloromycetin, Chloroptic)
Description	Binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. Available as solution (0.5%) or ointment (1%).
Adult Dose	Apply 1 gtt or 1-cm ribbon to inferior cul-de-sac of affected eye(s) or at site of skin incision; frequency of topical use is dictated by clinical setting
Pediatric Dose	Not established; however, can be administered as in adults
Contraindications	Documented hypersensitivity
Interactions	Administered concurrently with barbiturates, chloramphenicol serum levels may decrease, while barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Bone marrow toxicity, including aplastic anemia and death, have been reported following topical application of chloramphenicol; overgrowth of nonsusceptible bacterial may occur with prolonged use; medication may retard corneal would healing

Drug Name	Azithromycin (Zithromax)
Description	Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections.
Adult Dose	Day 1: 500 mg PO Days 2-5: 250 mg PO qd Alternatively, 1 g PO once
Pediatric Dose	<6 months: Not established >6 months: Day 1: 10 mg/kg PO once; not to exceed 500 mg/d Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In/Out Patient Meds:

• Treatment of ocular infection involves use of topical chloramphenicol or ciprofloxacin, both available as solution or ointment, following sample collection for culture and sensitivity. Frequency of application should correspond with severity of infection.
• Treatment of uveitis requires use of topical, periocular, or systemic corticosteroids. The mainstay of this treatment for anterior uveitis is topical prednisolone acetate. This often is combined with mydriatic-cycloplegic and analgesic agents.
• Other ocular conditions, such as serous retinal detachment, optic neuritis, and cranial neuropathies, are presumed to be due to immune factors. Treatment is directed toward the underlying infection and resultant inflammation.

Deterrence/Prevention:

• Improvement of environmental sanitation, including water supplies and sewage disposal, will sharply reduce the incidence of typhoid fever.
• Travelers to developing countries should avoid consuming untreated water, drinks served with ice, peeled fruits, and other food not served hot. Ice cream, unwashed produce, and shellfish are frequently reported causes of outbreaks of typhoid fever.
• Several vaccines are available and are effective in decreasing the risk of disease by 50-75%. However, persons who have been vaccinated should still exercise dietary precautions.

Complications:

• The most serious complication, intestinal bleeding or perforation, occurs in about 5% of patients. Bleeding usually is noted after the second week of illness, but perforation may occur unexpectedly after the patient has started to improve.
• Other complications include pneumonia, myocarditis, acute cholecystitis, and acute meningitis.
• Studies show that 1-5% of patients become chronic carriers, who harbor S typhi in their gall bladders. The risk of carrier status is correlated to underlying biliary pathology and co-infection with schistosomiasis.

Prognosis:

• Survival rates exceed 96% in developed countries but remain less than 90% in parts of the developing world despite antibiotic availability.

Patient Education:

• Observing dietary precautions and proper hygiene are important to patients during travel abroad, especially in high-risk areas.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Typhoid fever is a reportable disease in the United States.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ackers ML, Puhr ND, Tauxe RV, et al. Laboratory-based surveillance of Salmonella serotype Typhi infections in the United States: antimicrobial resistance on the rise. JAMA. May 24-31 2000;283(20):2668-73. [Medline].
• Akalin HE. Quinolones in the treatment of typhoid fever. Drugs. 1999;58 Suppl 2:52-4. [Medline].
• Bhan MK, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet. Aug 27-Sep 2 2005;366(9487):749-62. [Medline].
• Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ. Jul 8 2006;333(7558):78-82. [Medline].
• Davis TM, Makepeace AE, Dallimore EA, et al. Relative bradycardia is not a feature of enteric fever in children. Clin Infect Dis. Mar 1999;28(3):582-6. [Medline].
• Engels EA, Lau J. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2000;(2):CD001261. [Medline].
• Hanel RA, Araujo JC, Antoniuk A, et al. Multiple brain abscesses caused by Salmonella typhi: case report. Surg Neurol. Jan 2000;53(1):86-90. [Medline].
• Ismail TF. Rapid diagnosis of typhoid fever. Indian J Med Res. Apr 2006;123(4):489-92. [Medline].
• Jong EC. Travel immunizations. Med Clin North Am. Jul 1999;83(4):903-22, vi. [Medline].
• Julia J, Canet JJ, Lacasa XM, et al. Spontaneous spleen rupture during typhoid fever. Int J Infect Dis. 2000;4(2):108-9. [Medline].
• Khan M, Coovadia YM, Connolly C, et al. Influence of sex on clinical features, laboratory findings, and complications of typhoid fever. Am J Trop Med Hyg. Jul 1999;61(1):41-6. [Medline].
• Noyola DE, Fernandez M, Kaplan SL. Reevaluation of antipyretics in children with enteric fever. Pediatr Infect Dis J. Aug 1998;17(8):691-5. [Medline].
• Parry CM, Hien TT, Dougan G. Typhoid fever. N Engl J Med. Nov 28 2002;347(22):1770-82. [Medline].
• Thomsen LL, Paerregaard A. Treatment with ciprofloxacin in children with typhoid fever. Scand J Infect Dis. 1998;30(4):355-7. [Medline].
• World Health Organization. Background document: the diagnosis, treatment, and prevention of typhoid fever. Geneva, Switzerland: 2003.

Article Last Updated: Sep 29, 2006