Typhoid fever medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2], Aysha Aslam, M.B.B.S[3]

## Overview

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The mainstay of therapy for typhoid fever is antimicrobial therapy. Patients with uncomplicated typhoid fever are treated with either Azithromycin or a fluoroquinolone, whereas patients with severe or complicated forms of the disease are treated with either Ceftriaxone, Cefotaxime, or a fluoroquinolone.

## Medical therapy

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Antimicrobial therapy is recommended for all patients who develop typhoid fever. Adults and children suffering from typhoid fever require different courses of treatment.

### Adults

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* The mainstay of therapy in adults is the administration of fluoroquinolones due to rapid response rate.[1][2][3][4]
* Other agents used due to emerging resistance to fluoroquinolones are third-generation cephalosorins and Azithromycin.

#### Fluoroquinolones

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* Mainstay of therapy in regions which demonstrates antibiotic susceptiblity to fluoroquinolones[5]
* Bactericidial; concentrates intracellularly and in bile
* Early defervescence (less than 4 days)[6]
* Cure rate of 96 percent
* Relapse and carrier state of less than 2 percent[7][8]

#### Third-generation cephalosporins

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* First-line agent in adults with fluoroquinolone resistance[9]
* Main agents include ceftriaxone, cefixime, cefotaxime, and cefoperazone[10][11]
* Defervescence averages one week[5]
* Cure rate of 95 percent
* Relapse and carrier rate of less than 3 percent

#### Azithromycin

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* First-line agent in adults with fluoroquinolone or third-generation cephalsporin resistance[12][13]
* Excellent intracellular concentration[14][15]
* Defervescence of 4 to 6 days[5]
* Cure rate of 95 percent[16]
* Relapse and carrier rate of less than 3 percent

### Children

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* The mainstay of therapy for children in United States is third-generation cephaloporins due to suspected skeletal and tendinous side effects of fluoroquinolones in children.[17][18][19][20]
* First-line treatment for children in endemic areas is fluoroquinolones, especially in children with severe typhoid illness.[21][22][23]
* Other drugs that may be used for the treatment of typhoid fever in children include chlorampanicol, ampicillin, and trimethoprim sulfamethoxazole, depending on antibiotic susceptibility.[23]

### Pregnancy

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* Beta-lactam antibiotics and fluoroquinolones are considered safe to use during pregnancy.[24][25][5]

### Chronic carrier state

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* Fluoroquinolones may be considered the ideal therapy for chronic carrier state, in which patients show antibiotic sensitivity to fluoroquinolones.[26]

### Relapse

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* Instances of relapse are treated in the same way as an initial infection.[5]
* Optimal therapy depends on antibiotic susceptibility.[27]

### Resistance

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* Antibiotics such as ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole have commonly been used to treat typhoid fever in developed countries.[28] However, due to resistance to these antibiotics in highly endemic areas, these are no longer used as travelers have become infected with the resistant strains.[29]
* Typhoid that is resistant to these antibacterial agents is known as multidrug-resistant typhoid (MDR typhoid).[30][31]
* Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and other parts of Southeast Asia, including Pakistan, Bangladesh, Thailand, and Vietnam.[32]
* Current recommendations for testing antibiotic susceptibility of fluoroquinolone indicate that isolates should be tested simultaneously against ciprofloxacin (CIP) and nalidixic acid (NAL). Isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin," while isolates that are sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin." However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to ciprofloxacin (MIC 0.125-1.0 mg/l) would not be picked up by this method.[33][34][35]

## Antimicrobial regimen

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* Typhoid fever[36]

* Uncomplicated typhoid

* Preferred regimen (1) (fully susceptible): Fluoroquinolone (e.g., Ofloxacin 15 mg/kg PO qd for 5–7 days)
* Preferred regimen (2) (multi drug-resistant): Fluoroquinolone (Ofloxacin 15 mg/kg PO qd for 5–7 days)
* Preferred regimen (3) (quinolone-resistant): Azithromycin 8–10 mg/kg PO qd for 7 days
* Preferred regimen (4) (quinolone-resistant): Fluoroquinolone 20 mg/kg PO qd for 10-14 days
* Alternative regimen (1) (fully susceptible): Chloramphenicol 50–75 mg/kg PO qd for 14-21 days
* Alternative regimen (2) (fully susceptible): Amoxicillin 75–100 mg/kg PO qd for 14 days
* Alternative regimen (3) (fully susceptible): Trimethoprim–Sulfamethoxazole, 8 mg/kg (trimethoprim)– 40 mg/kg (sulfamethoxazole) PO qd for 14 days
* Alternative regimen (4) (multi drug-resistant): Azithromycin 8–10 mg/kg PO for 7 days
* Alternative regimen (5) (multi drug-resistant): Third-generation cephalosporin, e.g., Cefixime 20 mg/kg PO qd for 7-14 days
* Alternative regimen (6) (quinolone-resistant): Third-generation cephalosporin, e.g., Cefixime 20 mg/kg PO qd for 7-14 days

* Severe typhoid

* Preferred regimen (1) (fully susceptible): Fluoroquinolone (e.g., Ofloxacin 15 mg/kg IV qd for 10-14 days)
* Preferred regimen (2) (multi drug-resistant): Fluoroquinolone (Ofloxacin 15 mg/kg IV qd for 10-14 days)
* Preferred regimen (3) (quinolone-resistant): Ceftriaxone 60 mg/kg IV qd for 10-14 days
* Preferred regimen (4) (quinolone-resistant): Cefotaxime 80 mg/kg IV qd for 10-14 days
* Alternative regimen (1) (fully susceptible): Chloramphenicol 100 mg/kg PO qd for 14-21 days
* Alternative regimen (2) (fully susceptible): Ampicillin 100 mg/kg PO qd for 14-21 days
* Alternative regimen (3) (fully susceptible): Trimethoprim–Sulfamethoxazole, 8 mg/kg (trimethoprim)– 40 mg/kg (sulfamethoxazole) IV qd for 10-14 days
* Alternative regimen (4) (multi drug-resistant): Ceftriaxone 60 mg/kg IV qd for 10-14 days
* Alternative regimen (5) (multi drug-resistant): Cefotaxime 80 mg/kg IV qd for 10-14 days
* Alternative regimen (6) (quinolone-resistant): Fluoroquinolone 20 mg/kg IV qd for 10-14 days

* 1\. Uncomplicated typhoid fever[37]

* 1.1 Fully sensitive

* Preferred regimen (1): Ofloxacin 15 mg/kg/day for 5-7 days

* Preferred regimen (2): Ciprofloxacin 15 mg/kg/day for 5-7 days
* Alternative regimen (1): Chloramphenicol 50-75 mg/kg/day for 14-21 days
* Alternative regimen (2): Amoxicillin 75-100 mg/kg/day for 14 days
* Alternative regimen (3): TMP-SMX 8-40 mg/kg/day for 14 days

* 1.2 Multidrug resistance

* Preferred regimen (1): Fluoroquinolone 15 mg/kg/day for 5-7 days

* Preferred regimen (2): Cefixime 15-20 mg/kg/day for 7-14 days
* Alternative regimen (1): Azithromycin 8-10 mg/kg/day for 7 days
* Alternative regimen (2): Cefixime 15-20 mg/kg/day for 7-14 days

* 1.3 Quinolone resistance

* Preferred regimen (1): Azithromycin 8-10 mg/kg/day for 7 days

* Preferred regimen (2): Ceftriaxone 75 mg/kg/day for 10-14 days
* Alternative regimen: Cefixime 20 mg/kg/day for 7-14 days

* 2\. Severe typhoid fever

* 2.1 Fully sensitive

* Preferred regimen: Ofloxacin 15 mg/kg/day for 10-14 days
* Alternative regimen (1): Chloramphenicol 100 mg/kg/day for 14-21 days
* Alternative regimen (2): Amoxicillin 100 mg/kg/day for 14 days
* Alternative regimen (3): TMP-SMX 8-40 mg/kg/day for 14 days

* 2.2 Multidrug resistant

* Preferred regimen: Fluoroquinolone 15 mg/kg/day for 10-14 days
* Alternative regimen (1): Ceftriaxone 60 mg/kg/day for 10-14 days
* Alternative regimen (2): Cefotaxime 80 mg/kg/day for 10-14 days

* 2.3 Quinolone resistant

* Preferred regimen (1): Ceftriaxone 60 mg/kg/day for 10-14 days

* Preferred regimen (2): Cefotaxime 80 mg/kg/day for 10-14 days
* Alternative regimen: Fluoroquinolone 20 mg/kg/day for 7-14 days

## References

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1. ↑ Gotuzzo, Eduardo, and Carlos Carrillo. "Quinolones in typhoid fever." Infectious Diseases in Clinical Practice 3.5 (1994): 345-351.
2. ↑ White, Nicholas J., and Christopher M. Parry. "The treatment of typhoid fever." Current opinion in infectious disases 9.5 (1996): 298-302
3. ↑ Cao XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM (1999). "A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group". Pediatr Infect Dis J. 18 (3): 245–8. PMID 10093945.CS1 maint: Multiple names: authors list (link)
4. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1016/S0140-6736(13)62708-7 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
5. ↑ 5.0 5.1 5.2 5.3 5.4 Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ (2002). "Typhoid fever". N Engl J Med. 347 (22): 1770–82. doi:10.1056/NEJMra020201. PMID 12456854.CS1 maint: Multiple names: authors list (link)
6. ↑ Smith MD, Duong NM, Hoa NT, Wain J, Ha HD, Diep TS; et al. (1994). "Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever". Antimicrob Agents Chemother. 38 (8): 1716–20. PMC 284627. PMID 7986000.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ Thaver D, Zaidi AK, Critchley J, Azmatullah A, Madni SA, Bhutta ZA (2009). "A comparison of fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis". BMJ. 338: b1865. doi:10.1136/bmj.b1865. PMC 2690620. PMID 19493939.CS1 maint: Multiple names: authors list (link)
8. ↑ Girgis, Nabil I., et al. "Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance." Antimicrobial agents and chemotherapy 43.6 (1999): 1441-1444.
9. ↑ Parry CM (2004). "The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam". Trans R Soc Trop Med Hyg. 98 (7): 413–22. doi:10.1016/j.trstmh.2003.10.014. PMID 15138078.
10. ↑ Rastegar Lari A, Validi N, Ghaffarzadeh K, Shamshiri AR (1997). "In vitro activity of cefixime versus ceftizoxime against Salmonella typhi". Pathol Biol (Paris). 45 (5): 415–9. PMID 9296095.CS1 maint: Multiple names: authors list (link)
11. ↑ White, Nicholas J., and Christopher M. Parry. "The treatment of typhoid fever." Current opinion in infectious diseases 9.5 (1996): 298-302.
12. ↑ Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT; et al. (2008). "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. 3 (5): e2188. doi:10.1371/journal.pone.0002188. PMC 2374894. PMID 18493312.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
13. ↑ Meltzer E, Stienlauf S, Leshem E, Sidi Y, Schwartz E (2014). "A large outbreak of Salmonella Paratyphi A infection among israeli travelers to Nepal". Clin Infect Dis. 58 (3): 359–64. doi:10.1093/cid/cit723. PMID 24198224.CS1 maint: Multiple names: authors list (link)
14. ↑ Panteix G, Guillaumond B, Harf R, Desbos A, Sapin V, Leclercq M; et al. (1993). "In-vitro concentration of azithromycin in human phagocytic cells". J Antimicrob Chemother. 31 Suppl E: 1–4. PMID 8396080.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ Chinh, Nguyen Tran, et al. "A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever." Antimicrobial agents and chemotherapy 44.7 (2000): 1855-1859.
16. ↑ Butler, Thomas, et al. "Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India." Journal of Antimicrobial Chemotherapy 44.2 (1999): 243-250.
17. ↑ Burkhardt JE, Walterspiel JN, Schaad UB (1997). "Quinolone arthropathy in animals versus children". Clin Infect Dis. 25 (5): 1196–204. PMID 9402381.CS1 maint: Multiple names: authors list (link)
18. ↑ Phuong, Cao Xuan Thanh, et al. "A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children." The Pediatric infectious disease journal 18.3 (1999): 245-248.
19. ↑ Memon, IQBAL AHMAD, Abdul Gaffar Billoo, and HAMIDA IQBAL Memon. "Cefixime: an oral option for the treatment of multidrug-resistant enteric fever in children." Southern medical journal 90.12 (1997): 1204-1207.
20. ↑ Girgis NI, Sultan Y, Hammad O, Farid Z (1995). "Comparison of the efficacy, safety and cost of cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella typhi septicemia in children". Pediatr Infect Dis J. 14 (7): 603–5. PMID 7567290.CS1 maint: Multiple names: authors list (link)
21. ↑ Bethell DB, Hien TT, Phi LT, Day NP, Vinh H, Duong NM; et al. (1996). "Effects on growth of single short courses of fluoroquinolones". Arch Dis Child. 74 (1): 44–6. PMC 1511581. PMID 8660045.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
22. ↑ White NJ, Dung NM, Vinh H, Bethell D, Hien TT (1996). "Fluoroquinolone antibiotics in children with multidrug resistant typhoid". Lancet. 348 (9026): 547. PMID 8757168.CS1 maint: Multiple names: authors list (link)
23. ↑ 23.0 23.1 Stephens I, Levine MM (2002). "Management of typhoid fever in children". Pediatr Infect Dis J. 21 (2): 157–8. PMID 11840084.
24. ↑ Charnsangavej C (1979). "Occlusion of the right pulmonary artery by acute dissecting aortic aneurysm". AJR Am J Roentgenol. 132 (2): 274–6. doi:10.2214/ajr.132.2.274. PMID 105599.
25. ↑ Leung, Daryl, et al. "Treatment of typhoid in pregnancy." The Lancet 346.8975 (1995): 648.
26. ↑ Zavala Trujillo I, Quiroz C, Gutierrez MA, Arias J, Renteria M (1991). "Fluoroquinolones in the treatment of typhoid fever and the carrier state". Eur J Clin Microbiol Infect Dis. 10 (4): 334–41. PMID 1864294.CS1 maint: Multiple names: authors list (link)
27. ↑ Ferreccio, Catterine, et al. "Efficacy of ciprofloxacin in the treatment of chronic typhoid carriers." The Journal of infectious diseases 157.6 (1988): 1235-1239.
28. ↑ Herzog, Ch. "Chemotherapy of typhoid fever: a review of literature." Infection 4.3 (1976): 166-173.
29. ↑ White, Nicholas J., and Christopher M. Parry. "The treatment of typhoid fever." Current opinion in infectious diseases 9.5 (1996): 298-302
30. ↑ Rowe B, Ward LR, Threlfall EJ (1997). "Multidrug-resistant Salmonella typhi: a worldwide epidemic". Clin Infect Dis. 24 Suppl 1: S106–9. PMID [uid 8994789[uid]] Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
31. ↑ Ackers ML, Puhr ND, Tauxe RV, Mintz ED (2000). "Laboratory-based surveillance of Salmonella serotype Typhi infections in the United States: antimicrobial resistance on the rise". JAMA. 283 (20): 2668–73. PMID 10819949.CS1 maint: Multiple names: authors list (link)
32. ↑ Threlfall EJ, Ward LR (2001). "Decreased susceptibility to ciprofloxacin in Salmonella enterica serotype typhi, United Kingdom". Emerg Infect Dis. 7 (3): 448–50. doi:10.3201/eid0703.010315. PMC 2631792. PMID 11384525.
33. ↑ Cooke FJ, Wain J, Threlfall EJ (2006). "Fluoroquinolone resistance in Salmonella Typhi (letter)". Brit Med J. 333 (7563): 353&ndash, 4.CS1 maint: Multiple names: authors list (link)
34. ↑ Asna SM, Haq JA, Rahman MM (2003). "Nalidixic acid-resistant Salmonella enterica serovar Typhi with decreased susceptibility to ciprofloxacin caused treatment failure: a report from Bangladesh". Jpn J Infect Dis. 56 (1): 32–3. PMID 12711825.CS1 maint: Multiple names: authors list (link)
35. ↑ Slinger R, Desjardins M, McCarthy AE, Ramotar K, Jessamine P, Guibord C; et al. (2004). "Suboptimal clinical response to ciprofloxacin in patients with enteric fever due to Salmonella spp. with reduced fluoroquinolone susceptibility: a case series". BMC Infect Dis. 4: 36. doi:10.1186/1471-2334-4-36. PMC 521077. PMID 15380025.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
36. ↑ "TYPHOID FEVER".
37. ↑ "The diagnosis, treatment and prevention of typhoid fever" (PDF).

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