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 Anwar, M.B.B.S[3]

Overview

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 disease are treated with either Ceftriaxone, Cefotaxime, or a fluoroquinolone.

Medical therapy

  • Antimicrobial therapy is recommended among all patients who develop typhoid fever. Antimicrobial therapy used in adults and children is described as follows

Adults

  • The main stay of therapy in adults is use of floroquinolones due to rapid response rate[1][2][3][4]
  • Other agents used due to emerging resistance for floroquinolones are third generation cephalosorins and azithromycin.

Floroquinolones

  • Main stay of therapy in regions which demonstrates antibiotic susceptiblity to floroquinolones.[5]
  • Floroquinolones are bactericidial and concentrates intracellularly and in the bile.
  • Early defervescence less than 4 days[6]
  • Cure rate, 96 percent
  • Relapse and carrier state, less than 2 percent.[7][8]

Third generation cephalosporins

  • First line agent in adults having floroquinolone resistance.[9]
  • Agents used principally include ceftriaxone, cefixime, cefotaxime, and cefoperazone.[10][11]
  • Defervescence averages one week[5]
  • Cure rate 95 percent
  • Relapse and carrier rate less than 3 percent

Azithromycin

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

Children

  • The main stay of therapy in children in United States is third generation cephaloporins due to suspected potential side effect of floroquinolones in children affecting bones and tendons.[17][18][19]
  • However, first line treatment in endemic areas is floroquinolones especially in children with severe typhoid illness[20][21][22]
  • Other drugs which may be used for treatment of typhoid fever include chlorampanicol, ampicillin and trimethoprim sulfamethoxazole depending on antibiotic susceptibility.[22]

Resistance

  • Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and floroquinolones, have been commonly used to treat typhoid fever in developed countries. However, due to resistance to these antibiotics in highly endemic areas these are no longer used due to travelers getting infected with the resistant strains.
  • Resistance to ampicillin, chloramphenicol,and trimethoprim-sulfamethoxazole is common, and these agents have not been used as first line treatment now for almost 20 years.[23]
  • Typhoid that is resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid).[24][25]
  • Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia such as India, Pakistan, Bangladesh, Thailand or Vietnam.[26]
  • Current recommendations for testing antibiotic susceptibility of floroquinolone are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing 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.[27][28][29]

Antimicrobial regimen

  • 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[31]
  • 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 (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

  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.
  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).
  5. ↑ 5.0 5.1 5.2 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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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. ↑ 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.
  21. ↑ 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.
  22. ↑ 22.0 22.1 Stephens I, Levine MM (2002). "Management of typhoid fever in children". Pediatr Infect Dis J. 21 (2): 157–8. PMID 11840084.
  23. ↑ White, Nicholas J., and Christopher M. Parry. "The treatment of typhoid fever." Current opinion in infectious diseases 9.5 (1996): 298-302
  24. ↑ 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).
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ Cooke FJ, Wain J, Threlfall EJ (2006). "Fluoroquinolone resistance in Salmonella Typhi (letter)". Brit Med J. 333 (7563): 353&ndash, 4.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ "TYPHOID FEVER".
  31. ↑ "The diagnosis, treatment and prevention of typhoid fever" (PDF).

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