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U.S. Department of Health and Human Services

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Commentary on Non-Labeled Dosing of Oral Amoxicillin in Adults and Pediatrics for Post-Exposure Inhalational Anthrax

Recommendations from the Centers for Disease Control and Prevention (CDC)1 and the Johns Hopkins Working Group on Civilian Biodefense have included amoxicillin, among other drugs, for post-exposure prophylaxis (i.e., prevention) of inhalational anthrax following exposure to Bacillus anthracis.2 Although there are other approved antibacterial products, amoxicillin is also considered as a therapeutic option in those patients for whom approved products may be contraindicated and when the B. anthracis strain is susceptible to penicillin.

The Food and Drug Administration (FDA) recommends dosing for amoxicillin in adult and pediatric patients for penicillin-susceptible strains of B. anthracis, based on the principles discussed below, provided in the following table.

 Population Dose Every 8 hours
 Adults and Pediatric Patients ≥ 40 kg1000 mg 
 Pediatric Patients < 40 kg 25 mg/kg

 


Background

Several antimicrobial products are FDA-approved for post-exposure prophylaxis (PEP) of inhalational anthrax. In August 2000, FDA approved ciprofloxacin for this indication. Following the anthrax attacks in the fall of 2001, FDA published a notice in the November 2, 2001, Federal Register to clarify that doxycycline and penicillin G procaine are also approved for this indication, to provide dosing information, and to encourage application holders to add the dosing information to their product labeling.3 This notice was based upon review of relevant safety and pharmacokinetic data obtained by the FDA and from the results of an inhalational anthrax PEP study in rhesus macaques in which therapy with these drugs was utilized.4 FDA also approved levofloxacin for PEP of inhalational anthrax in November 2004.

FDA is aware of the various recommendations regarding amoxicillin and believes it is prudent to provide information about the basis for the proposed dosing recommendations and the supportive plasma pharmacokinetic data that have been collected for amoxicillin in adults and pediatric patients. The purpose is to provide clinicians with information that may be useful when making therapeutic decisions in the event of an intentional release of or accidental exposure to penicillin-susceptible strains of B. anthracis

Amoxicillin belongs to the class of penicillin antibiotics. It has been approved by the FDA to treat infections caused by susceptible gram-positive and gram-negative bacteria; however, amoxicillin is not approved by the FDA for use in post-exposure prophylaxis of inhalational anthrax. Preliminary data indicate B. anthracis isolates may contain constitutive and inducible beta-lactamases such as penicillinase and class B cephalosporinases. These enzymes often are present in naturally occurring B. anthracis isolates.5,6

 If susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) methods indicates B. anthracis isolates are susceptible to penicillin at minimum inhibitory concentrations (MICs) < 0.125 mcg/mL, the use of amoxicillin may be considered for post-exposure prophylaxis when other antibacterial drugs are not as safe to use, such as in pregnant women and children.7 

Dosing regimens of amoxicillin are based on the concept that the time above the MIC may correlate with successful clinical and/or microbiological outcomes for antibacterial drugs that exhibit time-dependent killing. Pharmacokinetic data were obtained from literature and new drug application (NDA) submissions for amoxicillin dosing in adults, pregnant women, and pediatric patients. A population pharmacokinetic approach was used to characterize the concentration time-course of amoxicillin. An advantage of using a population pharmacokinetic approach is that it can be used to simulate dosing regimens that may not have been studied previously. Various dose levels and dosing frequencies were simulated to explore the plasma amoxicillin concentration time-course under different dosing scenarios.

The recommended dosing regimens in adult and pediatric patients were based on the following considerations: 

  • The goal of amoxicillin dosing is to maintain plasma concentrations above an MIC of 0.125 mcg/mL. If this is not feasible, it is desirable to limit the amount of time that concentrations are below the MIC.

  • Dosing intervals of less than 8 hours are not practical and would likely lead to a lack of adherence to the regimen.

  • It is desirable to have consistent dosing recommendations in the entire adult population, regardless of pregnancy status.

  • The dosing frequency in pediatric patients should be the same as in adult patients.
     

Amoxicillin Pharmacokinetics in Adult Patients

Adult pharmacokinetic data were available in 20 healthy volunteers (10 men and 10 women) who received a single 750 mg dose of amoxicillin oral suspension. Previous studies have demonstrated a similar concentration time-course following oral suspension and capsules. Blood samples for measurement of amoxicillin concentration were obtained up to 24 hours post-dose. Data in pregnant women were obtained from a publication.8 The authors studied amoxicillin pharmacokinetics in 16 healthy pregnant women on three occasions: second trimester, third trimester, and 3 months postpartum. On each occasion, a single 500 mg oral dose was administered, and blood samples were collected up to 12 hours post-dose. The authors reported an increase in amoxicillin clearance during pregnancy. The population pharmacokinetic analysis therefore included a factor for pregnancy to increase clearance and volume of distribution.

Simulations were performed for different dose levels (e.g., 500 mg and 1000 mg) and dosing frequencies (e.g., 8, 6, and 4 hours). Simulations also explored the impact of a missed dose, which would be more likely to occur in patients receiving a 6 or 4 hour dosing regimen.

Simulations predicted that in 15% to 20% of adults receiving a dose of 500 mg every 8 hours, the amoxicillin concentrations would fall below the MIC during the dosing interval. These results are consistent with a study in another NDA in which 3 of 16 patients who received 500 mg amoxicillin with 125 mg clavulanate had plasma concentrations below the limit of quantitation at the end of the dosing interval. An even greater proportion of pregnant women will have inadequate amoxicillin concentrations due to increased clearance and volume of distribution. Approximately 60% of pregnant women in the second trimester were predicted to have trough concentrations below the MIC. As reported by Andrew MA et.al, the dosing interval for doses of 500 mg would have to be shortened to every 6 or even every 4 hours for amoxicillin concentrations to remain above the MIC in virtually all patients. Many patients, however, may fail to adhere to the more frequent dosing schedule.

A dose of 1000 mg every 8 hours was also simulated in adult patients. The simulations predict that about 20% of second-trimester women will have amoxicillin concentrations drop below the MIC during the dosing interval, but almost none of these 20% are predicted to have amoxicillin levels below the MIC for more than 2 hours. The clinical significance of these data is unknown. Non-pregnant adults are predicted to maintain amoxicillin concentrations above the MIC throughout the dosing interval. The results are presented in the table below. Based on the dosing constraints listed above, 1000 mg administered every 8 hours is the recommended dose in adult patients, regardless of pregnancy status.


Predicted Percentage of Patients with Amoxicillin Concentrations above MIC
for Dosing Regimen of 1000 mg every 8 hours

 

  Time Above MIC
0.125 mcg/mL)
Pregnancy Status

Trough (mcg/mL)
Median
[5th to 95th]

100% of dosing interval

 75% to 100% of dosing interval

 < 75% of dosing interval

2nd
Trimester

0.20
[0.06 – 0.53]

77%

23%

0%

3rd
Trimester

0.29
[0.10 – 0.71]

90%

10%

0%

Postpartum

0.29
[0.12 – 0.75]

93%

7%

0%

Non-Pregnant Adults

0.50
[0.16 – 1.36]

98%

2%

0%


Amoxicillin Pharmacokinetics in Pediatric Patients

Pediatric pharmacokinetic data were available in children (ages 1 month to 12 years) from an NDA for Augmentin (amoxicillin/clavulanate) oral suspension. Six subjects were administered 13.3 mg/kg amoxicillin (3.3 mg/kg clavulanate) every 8 hours for at least two days and five subjects were administered 22.5 mg/kg amoxicillin (3.2 mg/kg clavulanate) every 12 hours for at least two days. Various studies have shown that the presence of clavulanate does not lead to differences in systemic exposure to amoxicillin. Blood samples for measurement of amoxicillin concentration were obtained up to 12 hours post-dose. In order to understand the relationship between body weight and amoxicillin clearance, adult data were combined with pediatric data for population analysis. 

The amoxicillin dosing regimens in the study (13.3 mg/kg every 8 hours and 22.5 mg/kg every 12 hours) did not provide trough amoxicillin concentrations above the MIC in all pediatric patients. Nearly all patients receiving the dose of 22.5 mg/kg every 12 hours and 20% of the patients receiving the dose of 13.3 mg/kg every 8 hours had amoxicillin levels below the limit of assay quantitation at the end of the dosing interval. Simulations were therefore conducted to explore different dosing regimens. Body weights for 1000 children in each age group (≤2 years, 2 to ≤6 years, 6 to ≤12 years, and 12 to ≤16 years) were simulated using growth charts from the Centers for Disease Control and Prevention (CDC).9 

A dosing regimen of 25 mg/kg every 8 hours was one of the dosing regimens simulated. It was chosen in order to be similar to the 1000 mg every 8 hour regimen in adults. In this case, the pediatric dose is capped at 1000 mg for a 40 kg pediatric patient. The results in the table below suggest that the vast majority (≥ 95 %) of pediatric patients are predicted to have trough concentrations above the MIC with this dosing regimen. Therefore, the recommended dose in pediatric patients is 25mg/kg administered every 8 hours.


Predicted Percentage of Pediatric Patients with Amoxicillin Concentrations above MIC
for Dosing Regimen of 25 mg/kg every 8 hours 

 

  Time Above MIC
(0.125 mcg/mL)
Age Group (years)

Trough (mcg/mL)
Median
[5th to 95th]

100% of dosing interval

 75% to 100% of dosing interval

 < 75% of dosing interval

12 to ≤16

0.52
[0.15 – 1.68] 

98%

2%

0%

6 to ≤12

0.53
[0.15 – 1.60] 

97%

3%

0%

2 to ≤6

0.44
[0.12 – 1.24] 

95%

5%

0%

1 month to ≤ 2 years

0.57
[0.16 – 1.88] 

97%

3%

0%


References 

1. Centers for Disease Control and Prevention. Notice to Readers: Update: Interim Recommendations for Antimicrobial Prophylaxis for Children and Breastfeeding Mothers and Treatment of Children with Anthrax, November 2001. MMWR 2001 50(45):1014-1016.

2. Inglesby TV, et.al. 2002, Anthrax as a Biological Weapon: Updated Recommendations for Management. JAMA. 287(17):2236-52.

3. 66 FR 55679.

4. Friedlander, et.al., 1993, Postexposure Prophylaxis against Experimental Inhalation Anthrax. Journal of Infectious Diseases. 167:1239-42.

5. Centers for Disease Control and Prevention. Update: Investigation of Anthrax Associated with Intentional Exposure and Interim Public Health Guidelines, October 2001. MMWR 2001; 50(41):889 – 893.

6. Centers for Disease Control and Prevention. Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy, October 2001. MMWR 2001 50(42):909- 919.

7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria: Approved Guidelines—Second Edition CLSI document M45-A2, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2010. 

8. Andrew MA, Easterling TR, Carr DB, Shen D, Buchanan ML, Rutherford T, Bennett R, Vicini P, Hebert MF.  Amoxicillin Pharmacokinetics in Pregnant Women:  Modeling and Simulations of Dosage Strategies.  Clin Pharmacol Ther 2007;81:547-56.

9. http://www.cdc.gov/growthcharts/clinical_charts.htm