Antibiotic Treatment

Recommendations for the Use of Antibiotics for the Treatment of Cholera

Summary Recommendations

1. Oral or intravenous hydration is the primary treatment for cholera.
2. In conjunction with hydration, treatment with antibiotics is recommended for severely ill patients. It is also recommended for patients who have severe or some dehydration and continue to pass a large volume of stool during rehydration treatment. Antibiotic treatment is also recommended for all pregnant women and patients with comorbidities (e.g., severe acute malnutrition, HIV infection).
3. Antibiotics are given as soon as the patient can tolerate oral medication. The choice of antibiotic should be informed by local antibiotic susceptibility patterns. In most countries, doxycycline is recommended as first-line treatment for adults (including pregnant women) and children. If resistance to doxycycline is documented, azithromycin and ciprofloxacin are alternative options.
4.  During an epidemic or outbreak, antibiotic susceptibility should be monitored through regular testing of sample isolates from various geographic areas.
5. None of the guidelines recommend antibiotics as prophylaxis for cholera prevention, and all emphasize that antibiotics should be used in conjunction with aggressive hydration.
6. Education of healthcare workers, assurance of adequate supplies, and monitoring of practices are all important for appropriate dispensation of antibiotics.

Background

1. Cholera treatment is hydration
   Intravenous and oral 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%.
   • To help reduce resource requirements, consider using antibiotics for patients who are seriously dehydrated or have some dehydration with continued net fluid loss despite rehydration. By decreasing duration of diarrhea and volume of stool, antibiotics result in more rapid recovery and shorter lengths of inpatient stay, both of which contribute to more efficient use of resources during an outbreak.
   • The majority of published studies that explore effectiveness of antibiotics for cholera patients were done in patients who were adequately rehydrated. In these studies, there was no mortality, and therefore, the impact of antibiotics on mortality could not 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 an effective treatment for cholera and is superior to furazolidone, cholamphenicol,and sulfaguanidine in reducing cholera morbidity. Treatment with a single 300-mg dose of doxycycline has been shown to be equivalent to tetracycline treatment and is now recommended as first-line treatment in adults, including pregnant women, and in children. Previously, antibiotics of the tetracycline class were not recommended for pregnant women due to teratogenic effects, or in children due to dental discoloration. In a recent systematic review among pregnant women and young children receiving doxycycline, there was no correlation between the use of doxycycline and teratogenic effects or dental staining in children. Erythromycin is effective for cholera treatment and is also an appropriate alternative regimen for adults, including pregnant women, and children. Norfloxacin, trimethoprim-sulfamethoxazole (TMP-SMX), and ciprofloxacin 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.Resistance to tetracycline and other antimicrobial agents among Vibrio cholerae has been demonstrated in both endemic and epidemic cholera settings. Resistance can result from the accumulation of selected mutations over time, or from 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.
4. 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.
   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.
5. Summary of antibiotic treatment recommendations
   Antibiotics are recommended in cholera-infected patients with serious dehydration, or moderate dehydration with continuing net fluid losses despite rehydration. Antibiotics should not be used as prophylaxis for cholera prevention (except in specific institutional settings, such as prisons or psychiatric institutions), and should be used in conjunction with aggressive hydration 21. In addition, antimicrobial susceptibility testing should inform local drug choices. Antibiotic administration recommendations are provided below.

   Table showing the recommendations for Cholera treatment with antibiotics

   Age group	First-line drug choice	Alternate drug choices
   Children <12 years old	Doxycycline 2–4 mg/kg by mouth (per os, p.o.) single dose	Azithromycin 20 mg/kg (max 1 g) p.o. single dose, or ciprofloxacin 20 mg/kg (max 1 g) p.o. single dose
   Childen ≥12 years old and adults, including pregnant women	Doxycycline 300 mg p.o. single dose	Azithromycin 1 g p.o. single dose, or ciprofloxacin 1 g p.o. single dose

   * Please note, due to space constraints, dosage information is not included in this table. Dosage treatment guidance can be found on WHO’s cholera outbreak response website.

6. Considerations
   • Do not over-emphasize antibiotic treatment of cholera at the expense of the recommended primary treatment of oral and intravenous rehydration.
   • Doxycycline costs approximately $0.02 per 100-mg tablet. Azithromycin costs approximately $0.16 per 250-mg tablet.
   • Antibiotics can cause nausea and vomiting. Gastrointestinal side effects should be carefully monitored, especially in dehydrated patients.
   • In general, antibiotics should not be given to cholera patients with only some or no diarrhea and/or dehydration.
   • Prospective surveillance for antibiotic resistance among bacterial isolates from any outbreak is essential for understanding and minimizing the spread of resistance.