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Antibiotic Treatment

Recommendations for the Use of Antibiotics for the Treatment of Cholera

Summary Recommendations

  1. Oral or intravenous hydration is the mainstay of cholera treatment.
  2. In conjunction with hydration, treatment with antibiotics is recommended for severely ill patients. It is particularly recommended for patients who are severely or moderately dehydrated and continue to pass a large volume of stool during rehydration treatment. Antibiotic treatment is also recommended for all patients who are hospitalized.
  3. Antibiotic choices should be informed by local antibiotic susceptibility patterns. In most countries, Doxycycline is recommended as first-line treatment for adults, while azithromycin is recommended as first-line treatment for children and pregnant women. During an epidemic or outbreak, antibiotic susceptibility should be monitored through regular testing of sample isolates from various geographic areas.
  4. None of the guidelines recommend antibiotics as prophylaxis for cholera prevention, and all emphasize that antibiotics should be used in conjunction with aggressive hydration.
  5. Education of health care workers, assurance of adequate supplies, and monitoring of practices are all important for appropriate dispensation of antibiotics.

Background

  1. Mainstay of cholera treatment is hydration
    Intravenous 1 and oral 2 hydration are both associated with greatly decreased mortality and remain the mainstay of treatment for cholera.
  2. Antibiotic effectiveness for the treatment of cholera
    • Antibiotics have been used as an adjunct to hydration treatment for cholera since 1964. Findings from randomized controlled trials evaluated the effectiveness of selected antibiotics on three main outcomes: stool output, duration of diarrhea, and bacterial shedding.These studies compared outcomes for cholera patients who were given both intravenous (IV) fluids and antibiotic treatment with those given IV fluids only. Findings indicate that antibiotics reduced volume of stool output by 8-92%, duration of diarrhea by 50-56%, and duration of positive bacterial culture by 26-83% 3–7.
    • Antibiotic use for moderately and severely ill patients is also likely to reduce resource requirements. By decreasing duration of diarrhea and stool volume, antibiotics result in more rapid recovery and shorter lengths of inpatient stay, both of which contribute to optimizing resource utilization in an outbreak setting.
    • The majority of published studies exploring effectiveness of antibiotics for cholera patients have been done in patients who were adequately rehydrated. In these studies, there was no mortality and therefore the impact of antibiotics on mortality cannot be assessed. In the absence of adequate rehydration, antibiotics alone are not sufficient to prevent cholera mortality.
  3. Antibiotic regimens for the treatment of cholera
    Tetracycline has been shown to be effective treatment for cholera 2, 3 and is superior to furazolidone 8, cholamphenicol 9 and sulfaguanidine 9 in reducing cholera morbidity. Treatment with a single 300mg dose of doxycycline has shown to be equivalent to tetracycline treatment 10. Erythromycin is effective for cholera treatment, and appropriate for children and pregnant women 11. Orfloxacin 12, trimethoprim-sulfamethoxazole (TMP-SMX) 13, and ciprofloxacin 14 are effective, but doxycycline offers advantages related to ease of administration and comparable or superior effectiveness. Recently, azithromycin has been shown to be more effective than erythromycin and ciprofloxacin 15, 16 and is an appropriate first line regimen for children and pregnant women.
  4. Antibiotic resistance
    Resistance to tetracycline and other antimicrobial agents among V. cholerae has been demonstrated in both endemic and epidemic cholera settings. Resistance can be acquired through the accumulation of selected mutations over time, or the acquisition of genetic elements such as plasmids, introns, or conjugative elements, which confer rapid spread of resistance. A likely risk factor for antimicrobial resistance is widespread use of antibiotics, including mass distribution for prophylaxis in asymptomatic individuals. Antibiotic resistance emerged in previous epidemics in the context of antibiotic prophylaxis for household contacts of cholera patients 17, 18.
  5. Unanswered questions
    Inadequate information still exists with respect to antibiotics in the following areas:
    1. Effect of antibiotics on secondary transmission:
      • There are insufficient data examining the effect of antibiotics on secondary transmission of cholera. However, in published studies to date antibiotics have not been shown to decrease secondary transmission of cholera within households 19, 20.
    2. Utility of antibiotics when aggressive rehydration is not possible:
      • Because studies on antibiotic treatment for cholera were conducted in patients who received adequate rehydration, the effect of antibiotics in settings where this is not possible remains unclear.
  6. Summary of Antibiotic Treatment Guidelines
    Various organizations that participate in cholera responses recommend the use of antibiotics in cholera-infected patients with moderate or severe illness and who have begun IV hydration. None of the guidelines recommend antibiotics as prophylaxis for cholera prevention, and all emphasize that antibiotics should be used in conjunction with aggressive hydration. In addition, the guidelines recommend that antimicrobial susceptibility testing should inform local drug choices. Available guidelines are summarized below.

 

Guidelines for Cholera Treatment with Antibiotics

Organization

Recommendation

First-line drug choice

Alternate drug choices

Drug choices for special populations
World Health Organization 21 Antibiotic treatment for cholera patients with severe dehydration only Doxycycline Tetracycline Erythromycin is recommended drug for children
Pan American Health Organization 22 Antibiotic treatment for cholera patients with moderate or severe dehydration Doxycycline Ciprofloxacin Azithromycin Erythromycin or azithromycin recommended as first-line drugs for pregnant women and children Ciprofloxacin and doxycycline recommended as second-line drugs for children
International Centre for Diarrhoeal Disease Research, Bangladesh 23 Antibiotic treatment for cholera patients with some or severe dehydration

Doxycycline

Ciprofloxacin Azithromycin Cotrimoxazole

Erythromycin recommended as first-line drug for children and pregnant women
Medicins Sans Frontieres 24 Antibiotic treatment for severely dehydrated patients only Doxycycline Erythromycin Cotrimoxazole Chloramphenicol Furazolidone  

* Please note, due to space constraints, dosage information is not included in this table. Dosage guidance can be found by following the website links to the treatment guidance documents provided in the references section below 21-24.

  1. Considerations
    • Over-emphasizing antibiotics for treatment of cholera could divert resources from oral and intravenous rehydration.
    • Doxycycline costs approximately $0.02 per 100mg tablet. Azithromycin costs approximately $0.16 per 250mg tablet.
    • Antibiotics can cause nausea and vomiting. Gastrointestinal side effects should be carefully monitored, especially in dehydrated patients.
    • Antibiotics are not needed and should not be given to patients with cholera who have only mild or no diarrhea and dehydration.
    • Prospective surveillance for antibiotic resistance among bacterial isolates from any outbreak is essential for understanding and minimizing the spread of resistance.

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References

 

  1. O'Shaughnessy WB. Proposal of a new method of treating the blue epidemic cholera by the injection of highly oxygenized salts into the venous system. Lancet. 1831;17(432):366-71.
  2. Salazar-Lindo E , Seminario-Ottasco L , Carrillo-Parodi C , Gayasos- Villaflor A. The cholera epidemic in Peru [abstract]. In: Proceedings of the 27th Joint Conference on Cholera and Related Diarrheal Diseases, U.S.-Japan Cooperative Medical Science Program, Charlottesville, VA. 1991:9-13.
  3. Greenough WB, Gordon RS, Rosenberg IS, Davies BI, Benenson AS. Tetracycline in the treatment of cholera. Lancet. 1964;1(7329):355-7.
  4. Lindenbaum J, Greenhough WB, Islam MR. Antibiotic therapy of cholera. B World Health Organ. 1967;36:871-83.
  5. Rahaman MM, Majid MA, Alam AKMJ, Islam MR. Effects of doxycycline in actively purging cholera patients: a double-blind clinical trial. Antimicrob Agents Ch. 1976;10(4):610-12.
  6. Roy SK, Islam A, Ali R, Islam KE, Khan RA, Ara SH, Saifuddin NM, Fuchs GJ. A randomized clinical trial to compare the efficacy of erythromycin, ampicillin and tetracycline for the treatment of cholera in children. T Roy Soc Trop Med H. 1998;92:460-2.
  7. Kaushik JS, Gupta P, Faridi MMA, Das S. Single dose azithromycin versus ciprofloxacin for cholera in children: a randomized controlled trial. Indian Pediatr. 2010;47:309-315.
  8. Pierce NF, Banwell JG, Mitra RC, Caranosos GJ, Keimowitz RI, Thomas J, Mondal A. Controlled comparison of tetracycline and furazolidone in cholera. Brit Med J. 1968;3:277-80.
  9. Wallace CK, Anderson PN, Brown PC, Khanra SR, Lewis GW, Pierce NF, Sanyal SN, Segre GV, Waldman RH. Optimal antibiotic therapy in cholera. B World Health Organ. 1968;39:239-45.
  10. De S, Chaudhuri A, Dutta P, Dutta D, De SP, Pal SC. Doxycycline in the treatment of cholera. B World Health Organ. 1976;54:177-9.
  11. Burans JP, Podgore J, Mansour MM, Farah AH, Abbas S, Abu-Elyazeed R, Woody JN. Comparative trial of erythromycin and sulphatrimethoprim in the treatment of tetracycline-resistant Vibrio cholerae O1. T Roy Soc Trop Med H. 1989;83(6):836-8.
  12. Bhattacharya SK, Bhattacharya MK, Dutta P, Dutta D, De SP, Sikdar SN, Maitra A, Dutta A, Pal SC. Double-blind, randomized, controlled trial of norfloxacin for cholera. Antimicrob Agents Ch. 1990;34(5):939-40.
  13. Kabir I, Khan WA, Haider R, Mitra AK, Alam AN. Erythromycin and trimethoprim-sulphamethoxazole in the treatment of cholera in children. J Diarrhoeal Dis Res. 1996;14(4):243-7.
  14. Khan WA, Bennish ML, Seas C, Khan EH, Ronan A, Dhar U, Busch W, Salam MA. Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139. Lancet. 1996;348(9023):296-300.
  15. Khan WA, Saha D, Rahman A, Salam MA, Bogaerts J, Bennish ML. Comparison of single-dose azithromycin for childhood cholera: a randomized, double-blind trial. Lancet. 2002;360:1722-7.
  16. Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish ML. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med. 2006;354(23):2452-62.
  17. Weber JT, Mintz ED, Cañizares R, Semiglia A, Gomez I, Sempértegui R, Dávila A, Greene KD, Puhr ND, Cameron DN, Tenover FC, Barrett TJ, Bean NH, Ivey C, Tauxe RV, Blake PA. Epidemic cholera in Ecuador: multidrug-resistance and transmission by water and seafood. Epidemiol Infect. 1994;112(1):1-11.
  18. Towner KJ, Pearson NJ, Mhalu FS, O'Grady F. Resistance to antimicrobial agents of Vibrio cholerae E1 Tor strains isolated during the fourth cholera epidemic in the United Republic of Tanzania. B World Health Organ. 1980;58(5):747-51.
  19. Weil AA, Khan AI, Chowdhury F, Larocque RC, Faruque AS, Ryan ET, Calderwood SB, Qadri F, Harris JB. Clinical outcomes in household contacts of patients with cholera in Bangladesh. Clin Infect Dis. 2009;49(10):1473-9.
  20. Echevarria J, Seas C, Carrillo C, Mostorino R, Ruiz R, Gotuzzo E. Efficacy and tolerability of ciprofloxacin prophylaxis in adult household contacts of patients with cholera. Clin Infect Dis. 1995;20(6):1480-4.
  21. WHO. Cholera Outbreak: Assessing the Outbreak Response and Improving Preparedness. [PDF - 88 pages].
  22. PAHO. Recommendations for clinical management of cholera. [PDF - 8 pages]. November 2010.
  23. Cholera Outbreak Training and Shigellosis (COTS) Program — All Chapters. [PDF – 87 pages]
  24. Médecins Sans Frontières. Cholera Guidelines, 2nd Edition. [PDF – 157 pages]. 2004.

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