Medication

Antibiotics

Class Summary

Since 2016, Salmonella typhi, and to a lesser extent Salmonella paratyphi, have progressively developed resistance to the previously effective antibiotics. Multi-drug-resistant (MDR) typhoid is resistant to ampicillin, trimethoprim sulfamethoxazole, and chloramphenicol. XDR – typhoid has become resistant to chloramphenicol ampicillin, floroquinolones, and third generation cephalosporins. Only azithromycin, members of the carbapenem class, and tigecycline remain effective against XDR isolates.

Since recognition of XDR typhoid fever has been documented in the United States among those who did not travel internationally, appropriate treatment for this disease should consist of azithromycin with or without addition of a carbapenem depending on the severity of the clinical presentation.^{[49, 50, 51]}

Development of MDR and XDR strains has occurred primarily in Pakistan. Most likely, poor sanitation and overuse of antibiotics for the treatment of other infections have been the major reasons for the rapid rise of resistance in Pakistan and other similar countries.The marked increase in density of the urban population in Karachi and other cities clearly facilitates spread of these variants.

The medical complications of COVID-19 have already stressed the medical resources of Pakistan. Many do not want to risk perceived, possible exposure to this virus at various healthcare sites. The marked increase in population density in large cities such as Karachi has facilitated the spread of this pathogen.

Mass immunization campaigns to control typhoid have been thwarted because of religious and cultural prejudices.

Azithromycin (Zithromax)

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Treats mild to moderate microbial infections. Administered PO at 10 mg/kg/d (not exceeding 500 mg), appears to be effective to treat uncomplicated typhoid fever in children 4-17 y. Confirmation of these results could provide an alternative for treatment of typhoid fever in children in developing countries, where medical resources are scarce.

Class Summary

Dexamethasone may decrease the likelihood of mortality in severe typhoid fever cases complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has been definitively ruled out by cerebrospinal fluid studies. To date, the most systematic trial of this has been a randomized controlled study in patients aged 3-56 years with severe typhoid fever who were receiving chloramphenicol therapy. This study compared outcomes in 18 patients given placebo with outcomes in 20 patients given dexamethasone 3 mg/kg IV over 30 minutes followed by dexamethasone 1 mg/kg every 6 hours for 8 doses. The fatality rate in the dexamethasone arm was 10% versus 55.6% in the placebo arm (P =.003).^[52]

Nonetheless, this point is still debated. A 2003 WHO statement endorsed the use of steroids as described above, but reviews by eminent authors in the New England Journal of Medicine (2002)^[4]and the British Medical Journal (2006)^[53]do not refer to steroids at all. A 1991 trial compared patients treated with 12 doses of dexamethasone 400 mg or 100 mg to a retrospective cohort in whom steroids were not administered. This trial found no difference in outcomes among the groups.^[54]

The data are sparse, but the authors of this article agree with the WHO that dexamethasone should be used in cases of severe typhoid fever.

Dexamethasone (Decadron)

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Prompt administration of high-dose dexamethasone reduces mortality in patients with severe typhoid fever without increasing incidence of complications, carrier states, or relapse among survivors.

Tigecycline (Tygacil)

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100mg IVloading

Follow-up

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Life cycle of Salmonella typhi.

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Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever^{[2, 33, 34, 35, 36, 37]}

	Incubation	Week 1	Week 2	Week 3	Week 4	Post
Systemic					Recovery phase or death (15% of untreated cases)	10%-20% relapse; 3%-4% chronic carriers; long-term neurologic sequelae (extremely rare); gallbladder cancer (RR=167; carriers)
Stepladder fever pattern or insidious onset fever		Very common^a	Very common
Acute high fever		Very rare^b
Chills		Almost all^c
Rigors		Uncommon
Anorexia		Almost all
Diaphoresis		Very common
Neurologic
Malaise		Almost all	Almost all	Typhoid state (common)
Insomnia			Very common
Confusion/delirium		Common^d	Very common
Psychosis		Very rare	Common
Catatonia		Very rare
Frontal headache (usually mild)		Very common
Meningeal signs		Rare^e	Rare
Parkinsonism		Very rare
Ear, nose, and throat
Coated tongue		Very common
Sore throat^f
Pulmonary
Mild cough		Common
Bronchitic cough		Common
Rales		Common
Pneumonia		Rare (lobar)	Rare	Common (basal)
Cardiovascular
Dicrotic pulse		Rare	Common
Myocarditis		Rare
Pericarditis		Extremely rare^g
Thrombophlebitis				Very rare
Gastrointestinal
Constipation		Very common	Common
Diarrhea		Rare	Common (pea soup)
Bloating with tympany		Very common (84%)^[37]
Diffuse mild abdominal pain		Very common
Sharp right lower quadrant pain		Rare
Gastrointestinal hemorrhage		Very rare; usually trace	Very common
intestinal perforation				Rare
Hepatosplenomegaly		Common
Jaundice		Common
Gallbladder pain		Very rare
Urogenital
Urinary retention		Common
Hematuria		Rare
Renal pain		Rare
Musculoskeletal
Myalgias	Very rare
Arthralgias	Very rare
Rheumatologic
Arthritis (large joint)	Extremely rare
Dermatologic
Rose spots		Rare
Miscellaneous
Abscess (anywhere)		Extremely rare	Extremely rare	Extremely rare
^a Very common: Symptoms occur in well over half of cases (approximately 65%-95%). ^b Very rare: Symptoms occur in less than 5% of cases. ^c Almost all: Symptoms occur in almost all cases. ^d Common: Symptoms occur in 35%-65% of cases. ^e Rare: Symptoms occur in 5%-35% of cases. ^f Blank cells: No mention of the symptom at that phase was found in the literature. ^g Extremely rare: Symptoms have been described in occasional case reports.

Table 2. Sensitivities of Cultures^{[2, 39, 40, 41]}

	Incubation	Week 1	Week 2	Week 3	Week 4
Bone marrow aspirate (0.5-1 mL)		90% (may decrease after 5 d of antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate culture	40%-80%		~20%	Variable (20%-60%)
Urine		25%-30%, timing unpredictable

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Author

John L Brusch, MD, FACP Corresponding Faculty Member, Harvard Medical School

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard B Brown, MD, FACP Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Roberto Corales, DO, AAHIVS Senior Director, HIV Medicine and Clinical Research, Trillium Health

Roberto Corales, DO, AAHIVS is a member of the following medical societies: American Medical Association, International AIDS Society, American Osteopathic Association

Disclosure: Nothing to disclose.

Steven K Schmitt, MD Staff Physician, Department of Infectious Disease, Cleveland Clinic

Steven K Schmitt, MD is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Thomas Garvey, MD, JD † Primary Care Physician, Burlington Medical Associates; Co-Chair, Medical Advisory Committee For the Elimination of Tuberculosis

Thomas Garvey, MD, JD is a member of the following medical societies: American College of Legal Medicine, American College of Physicians, American Society of Law, Medicine & Ethics

Disclosure: Nothing to disclose.

Typhoid Fever Medication

Antibiotics