Commentary on Non-Labeled Dosing of Oral Amoxicillin in
Adults and Pediatrics for Post-Exposure Inhalational Anthrax
SUMMARY
Recent recommendations from the Centers for Disease Control and Prevention (CDC) and the Johns Hopkins Working Group on Civilian Biodefense have included
amoxicillin, among other drugs, that may be used for prophylaxis/prevention of inhalational anthrax following exposure to Bacillus anthracis. Although the CDC considers ciprofloxacin and doxycycline as first line agents, amoxicillin is also considered as a therapeutic option in those patients where ciprofloxacin and doxycycline may be contraindicated.
Currently, only ciprofloxacin has been approved by the FDA specifically for prophylaxis/prevention of inhalational anthrax following exposure to Bacillus anthracis. Doxycycline and procaine penicillin G are labeled for treatment of disease caused by B. anthracis. A recent Federal Register notice by the FDA provided additional information on the use of doxycycline and intramuscular (IM) procaine penicillin G for prophylaxis/prevention of inhalational anthrax following exposure to Bacillus anthracis. This action was based upon review of relevant safety and pharmacokinetic data obtained by the FDA and from the results of a post-exposure inhalational anthrax study in rhesus monkeys where therapy with these drugs was utilized
(Friedlander, et.al. (1)).
Amoxicillin has not been approved by the FDA for use in post-exposure inhalational anthrax and has not been evaluated in a non-human primate study similar to that as conducted by
Friedlander, et.al. (1). However, the FDA is aware of the various recommendations regarding amoxicillin and believes it would be prudent to provide information about the safety and plasma pharmacokinetic data that have been collected for amoxicillin in adults and pediatric patients. The overall purpose is to provide clinicians with information that may be useful when making therapeutic decisions in the unfortunate event of terrorist use of penicillin-susceptible strains of B. anthracis.
Dosing regimens for amoxicillin for post-exposure inhalational anthrax have been derived for adults and pediatric patients based on the following:
- Plasma concentration data obtained at peak and trough for penicillin following IM administration of procaine penicillin G in a post-exposure efficacy study in rhesus monkeys exposed to B. anthracis via inhalation ((1); Kelly, et. al. (2)). In the monkeys treated with IM procaine penicillin G every 12hr, peak and trough penicillin concentrations ranged from 2 to
3.5mg/mL and 0.4 to 1.1mg/mL, respectively.
- MIC values for penicillin-susceptible strains of B. anthracis reported from the literature, i.e., 0.015 to
0.5mg/mL (2) and from the CDC/NCCLS for 11 isolates associated with recent intentional exposures in the eastern U.S. (penicillin: <0.06 to
0.12mg/mL; amoxicillin: <0.03mg/mL).
- Pharmacokinetic data obtained from the literature and, where applicable, from NDA submissions, for amoxicillin in adults and pediatric patients.
- The concept that Time Above MIC (TMIC) may correlate with successful clinical and/or microbiological outcomes for antibiotics such as the penicillins and other
beta-lactams that exhibit time-dependent bacterial killing (Craig (3), Turnidge (4)). However, in the absence of obtaining complete plasma antibiotic concentration vs. time profiles, trough concentrations at the end of the dosing interval, in addition to peak concentrations, may be useful in approximating the TMIC. In the primate efficacy study of post-exposure inhalational anthrax, all animals (10/10) survived during the 30-day treatment course with IM procaine penicillin G given every 12 hours (1), and the majority of animals had trough penicillin plasma concentrations of
0.5mg/mL and above during this course (2). Thus, targeted ranges for peak and trough plasma levels of amoxicillin following oral administration for post-exposure inhalational anthrax were set at 2 to
3.5mg/mL and _0.5mg/mL, respectively. The trough of _0.5mg/mL is a conservative estimate and was selected since this represented the upper MIC value reported in the literature for penicillin (2). In addition, based on the
CDC/NCCLS report for penicillin susceptibility, trough plasma concentrations as low as
0.12mg/mL at the end of the dosing interval may be adequate and this was also taken into consideration.
The table below summarizes the dosing regimens of amoxicillin for adults and pediatrics that should provide an adequate time of systemic exposure (plasma concentrations) above the MIC for susceptible isolates of B. anthracis over the majority of the dosing interval.
Drug
|
Adult Regimen
|
Pediatric Regimen
|
Comments
|
Amoxicillin
|
500mg Q 8hr
|
³40 kg:
500mg Q 8hr
<40 kg:
15mg/kg Q 8hr*
(total 45 mg/kg/day)
|
*This is the minimum amoxicillin dose for pediatric patients weighing <40 kg. Doses <45mg/kg/day and dosing intervals greater than every 8 hr should not be used.
|
AMOXICILLIN
Amoxicillin Pharmacokinetics in Adults
Amoxicillin offers an advantage over oral penicillin (penicillin V) and ampicillin in that it has greater oral
bioavailability. Approximately 74-92% of a single dose of amoxicillin is absorbed while approximately 60-70% of an oral penicillin V dose and 30-55% of an oral ampicillin dose are absorbed. Peak serum amoxicillin concentrations
(Cmax) are reached 1-2 hours after an oral dose of the capsules, film-coated tablets, chewable tablets, or oral suspension in fasting and non-fasting adults. Non-linearity in absorption of amoxicillin has been reported when increasing doses of 250mg, 500mg, and 1000mg of amoxicillin were administered to fasting adults. A significant reduction in the percentage of the dose absorbed was observed for the 1000mg dose (5).
Literature Cmax values for amoxicillin range from 3.5 - 5mg/mL and 5.5 -
11mg/mL following single oral 250mg and 500mg doses, respectively (Table 1). Elimination is primarily via the kidneys and is rapid, with a relatively short half-life of approximately 1 hour. The recently reported MIC values from the
CDC/NCCLS for B. anthracis are <0.03mg/mL for amoxicillin and <0.06 -
0.12mg/mL for penicillin. Although there was limited information on the trough concentrations of amoxicillin in the literature reviewed, one can safely estimate the plasma/serum concentrations to be above the upper end of the penicillin MIC (0.12 mg/ml) for at least approximately 6 hrs following the 500mg Q 8hr dosage regimen. This represents 75% of the 8-hour dosing interval (~6 half-lives) following this regimen.
Table 1. Mean (±SD) Plasma Concentrations (mg/mL) of Amoxicillin Following Oral Doses of 250mg and 500mg to Healthy Adult Subjects
250 mg
|
500 mg
|
Reference
|
Cmax 3.4
|
Cmax 6.8
|
Bodey & Nance (6)
|
Not Reported
|
Cmax 10.4 ± 3.8
|
Kosmidis, et. al. (7)
|
Cmax 5.3 ± 11.1
|
Cmax 10.8 ± 2.9
|
Croydon & Sutherland (8)
|
Cmax 3.0-3.2
|
Cmax 7.6-7.7
Conc. @ 8hr: 0.3
|
Neu (9)
|
Not Reported
|
Cmax 7.6
|
Gordon, et.al. (10)
|
Day 1
Cmax 4.5 ± 2.1
Conc. @ 6hr 0.44 ± 0.40
Conc. @ 8hr 0.05 ± 0.05
Day 8
Cmax 5.6 ± 1.8
Conc. @ 6hr 0.15 ± 0.37
Conc. @ 8hr 0.14 ± 0.20
|
Day 1
Cmax 7.8 ± 4.8
Conc. @ 6hr 0.64 ± 0.76
Not Reported @ 8hr
Day 8
Cmax 7.6 ± 1.6
Conc. @ 6hr 0.35 ± 0.38
Not Reported @ 8hr
|
Brusch, et. al. (11)
|
Cmax 3.8
|
Cmax 5.9
|
Spyker, et. al. (5)
|
Not reported
|
Cmax 6.2
|
Philipson, et. al. (12)
|
Cmax 3.5
|
Not Reported
|
Zarowny, et. al. (13)
|
Cmax 4.9
|
Cmax 7.7
|
Oliveira, et. al. (14)
|
The Question of Dosing Frequency for Post-Exposure Inhalational Anthrax
The issue of whether the 875mg Q 12hr amoxicillin regimen would provide adequate plasma levels over the entire dosing interval as compared to those provided by the 500mg Q 8hr regimen was addressed. Plasma amoxicillin concentration - time data was obtained for adults receiving Q 12hr and Q 8hr regimens of Augmentin
(amoxicillin + clavulanic acid) from an NDA submission (15). Data from two pharmacokinetic studies in healthy adult subjects were reviewed (Study 1 and Study 2), each having similar study design and methods (i.e., randomized, 2-way crossover). In each study subjects received the 875mg
amoxicillin/125mg clavulanate Q 12hr regimen on one occasion (i.e., 1 dose every 12 hrs) and the 500mg
amoxicillin/125mg clavulanate Q 8hr regimen on another occasion (i.e., 1 dose every 8 hrs). The plasma amoxicillin concentration data at Cmax and at the end of the respective dosing intervals are summarized in Table 2 below.
Table 2. Amoxicillin Plasma Concentrations Following Oral Dosage Regimens of Augmentin to Healthy Adult Subjects; Data Expressed as Mean _ SD (Range)
Dosage Regimen
|
Mean Cmax
(mg/mL)
|
Mean "Trough" Conc. *
(mg/mL)
|
Study 1
|
875mg amoxicillin / 125mg clavulanate
Q 12hr
(N=15)
|
8.3 ± 2.2
(5.2 - 12.9)
|
Conc. @ 8hr: 0.54 ± 0.57
(<0.1 - 2.26)**
n=1 <0.1
Conc. @ 12hr: 0.05 ± 0.09
(<0.1 - 0.23)
n=11 <0.1
|
500mg amoxicillin / 125mg clavulanate
Q 8hr
(N=16)
|
5.2 ± 1.3
(3.4 - 7.9)
|
Conc. @ 6hr: 0.84 ± 0.54
(0.14 - 2.15)
Conc. @ 8hr: 0.25 ± 0.19
(<0.1 - 0.55)
n=3 <0.1
|
Study 2
|
875mg amoxicillin / 125mg clavulanate
Q 12hr
(N=14)
|
11.6 ± 2.8
(8.8 - 18.0)
|
Conc. @ 8hr: 0.27 ± 0.15
(<0.1 - 0.53)
n=2 <0.1
Conc. @ 12hr: 0.01 ± 0.04
(<0.1 - 0.14)
n=13 <0.1
|
500mg amoxicillin / 125mg clavulanate
Q 8hr
(N=14)
|
7.2 ± 2.3
(4.6 - 14.1)
|
Conc. @ 6hr: 0.56 ± 0.29
(<0.1 - 1.03)
n=1 @ <0.1
Conc. @ 8hr: 0.16 _ 0.11
(<0.1 - 0.32)
n=3 <0.1
|
*Trough concentrations after either the 2nd (875mg Q 12hr) or 3rd (500mg Q 8hr) dose
**Lower Limit of Quantitation (LLOQ) of the assay was 0.1mg/mL
The data from the table shows that, while the Cmax for amoxicillin is higher with the 875mg Q 12hr regimen, the trough concentrations at 12 hours postdose are below the upper limits of the MIC of B. anthracis that have been reported for penicillin (i.e., 0.5mg/mL and
0.12mg/mL).
In fact, for the majority of subjects receiving the 875mg Q 12hr regimen in these studies, the concentration of amoxicillin was below the limit of assay quantitation at 12 hours postdose (i.e., 11/15 subjects (73%) and 13/14 subjects (93%) at <0.1mg/mL). However, at 8 hours after the 875mg Q 12hr regimen, concentrations are adequate with respect to the aforementioned MIC's for B. anthracis for the majority of subjects. Thus, with the 875mg Q 12hr regimen, plasma levels of amoxicillin may not be able to cover the penicillin/amoxicillin MIC's for approximately 4 hours of the 12-hour dosing interval (adequate coverage for only 8 hrs out of 12 hrs).
For the 500mg Q 8hr regimen, the Cmax values for amoxicillin are still acceptable as well as trough concentrations at 6 to 8 hours postdose. Note that with the 500mg Q 8hr regimen, only a few subjects have plasma amoxicillin concentrations below the limit of assay quantitation at the end of the dosing interval (i.e., 3/16 subjects (19%) and 3/14 subjects (21%) <0.1mg/mL at 8 hours). Thus, with the 500mg Q 8hr regimen, amoxicillin plasma levels may not be able to cover the penicillin/amoxicillin MIC's for only 2 hours of the 8-hour dosing interval (adequate coverage for 6 to 8 hrs out of 8 hrs).
Due to the short half-life of amoxicillin and the potential for reduced absorption with increasing dose, it is not likely that a Q 12hr dosing regimen of a higher dose will provide adequate concentrations above the MIC's for B. anthracis over a clinically acceptable time during the dosing interval. This is because nearly all of amoxicillin is eliminated in about 7 half-lives (~99% in 7 hrs). Also, with 500 mg Q 8hr multiple dosing, there should be no accumulation of the drug since the half-life is very short.
Comments on Clavulanic Acid
Amoxicillin and clavulanate in fixed ratios are currently marketed in the U.S. under the trade name Augmentin®. Various studies have shown that the presence of clavulanate in the combination product does not lead to differences in systemic exposure to amoxicillin. Similarly, amoxicillin does not affect the systemic exposure to clavulanate (NDA 50-720 (15), Hampel, et. al. (16); NDA 50-754 (17)).
Conclusions
Based on the information obtained and reviewed, an oral dosage regimen of 500mg Q 8hr of amoxicillin administered to adults and pediatric patients weighing 40 kg and above should yield an adequate time of
systemic exposure (plasma concentrations) of amoxicillin that is above the MIC for susceptible isolates of B.anthracis for the majority of the dosing interval (i.e., 75%-100%).
Amoxicillin Pharmacokinetics in Pediatrics
Limited pharmacokinetic data was obtained from the literature for amoxicillin in children. Table 3 below summarizes the plasma amoxicillin concentrations following single doses of 15 mg/kg and 25 mg/kg orally in children from 4 months to 4 years of age. Although the data from these studies are limited to plasma concentrations out to 6 hrs postdose, these results indicate that the concentrations at 6 hrs are similar for the 15mg/kg and 25mg/kg doses. Additionally, plasma amoxicillin concentrations at 8 hrs would be expected to be greater than the MIC values reported for amoxicillin and penicillin reported by the CDC/NCCLS (i.e., <0.03mg/mL and <0.06 to 0.12mg/mL, respectively), based on the plasma half-life of approximately 1 to 2 hrs determined in these studies.
Table 3. Amoxicillin Plasma Concentrations Following Single Oral Doses of Amoxicillin to Children; Data Expressed as Mean ± SD (Range)
Dose
mg/kg
|
Fed / Fasting*
|
Mean "Peak"
Conc.
(mg/mL)
|
Mean "Trough"
Conc.
(mg/mL)
|
Comments / References
|
15
|
Fasting
|
5.4 ± 0.76
@ 1hr
(Range: 2.4 - 8.5)
|
0.6 ± 0.25
@ 6hrs
(Range: 0.14 - 3.3)
|
N=13
T_ 1.1 hr
|
All Children
Ages 4 months -
4 years;
mean 27 months
(2.3 yr.)
Ginsburg, et. al. (18)
|
15
|
Fed
|
3.2 ± 2.6
@ 2hrs
(Range: 2.3 - 4.5)
|
0.7 ± 0.11
@ 6hrs
(Range: 0.16 - 1.2)
|
N=13
T_ 1.8 hr
|
25
|
Fasting
|
8.9 ± 1.4
@ 1hr
(Range: 3.6 - 15.4)
|
0.6 ± 0.20
@ 6hrs
(Range: 0.01 -1.7)
|
N=11
T_ 1.2 hr
|
25
|
Fed
|
7.9 ± 1.7
@ 1hr
(Range: 1.8 - 13.2)
|
0.7 ± 0.20
@ 6hrs
(Range: 0.18 - 1.3)
|
N=11
T_ 1.2 hr
|
*Fed = drug administration followed immediately by 4 oz. milk or formula; Fasting = no food or milk substance 2 hrs before and 2 hrs after drug administration
The Question of Dosing Frequency for Post-Exposure Inhalational Anthrax
Similar to adults, this issue was addressed for pediatric patients. Plasma amoxicillin concentration - time data was obtained for children receiving Q 12hr and Q 8hr regimens of Augmentin oral suspension (amoxicillin / clavulanic acid) from an NDA submission (19). Pharmacokinetic data from one study in pediatric patients ranging in age from 1 month to 12 years of age was reviewed. In this study, pediatric patients received 45/6.4mg/kg/day amoxicillin / clavulanate suspension Q 12hr for 10 days and another group received 40/10mg/kg/day amoxicillin / clavulanate suspension Q 8hr for 10 days. The plasma amoxicillin concentration data at Cmax and at the end of the respective dosing intervals are summarized in Table 4 below.
Table 4. Amoxicillin Plasma Concentrations Following Oral Dosage Regimens of Augmentin Suspension to Pediatric Patients; Data Expressed as Mean _ SD (Range)
Dosage Regimen
|
Mean Cmax*
(mg/mL)
|
Mean "Trough" Conc.*
(mg/mL)
|
Comments
|
22.5mg/kg amoxicillin / 3.2mg/kg clavulanate Q 12hr
45/6.4mg/kg/day
(N=5)
|
12.0
(6.6 - 15.3)
|
Conc. @ 8hr: 0.34 ± 0.20
(<0.2 - 0.52)**
n=1 <0.2
Conc. @ 12hr:
n=4 <0.2
|
N=4 children 6 to 12 years of age
N=1 child 4 months of age
|
13.3mg/kg amoxicillin / 3.3mg/kg clavulanate Q 8hr
40/10mg/kg/day
(N=6)
|
7.3
(3.2 - 9.1)
|
Conc. @ 6hr: 0.91 ± 0.98
(<0.2 - 2.66)
n=1 <0.2
Conc. @ 7hr: 0.68 ± 0.98
(<0.2 - 2.60)
n=2 <0.2
Conc. @ 8hr: 0.47 ± 0.81
(<0.2 - 2.08)
n=3 <0.2
|
N=4 children 2 to 9 years of age
N=2 children: 1 month and 9 months of age
|
*Peak and trough concentrations after at least 2 days of either regimen; total duration of treatment = 10 days
**Lower Limit of Quantitation (LLOQ) of the assay was 0.2mg/mL
The data from this table shows that the amoxicillin / clavulanate regimen of 22.5/3.2 mg/kg Q 12hr did not produce quantifiable plasma amoxicillin concentrations at the end of the dosing interval (i.e., 12 hours). Note that nearly all patients had plasma amoxicillin concentrations below the lower limit of assay quantitation at 12 hours postdose (i.e., 4/5 patients (80%) at <0.2mg/mL). However, at 8 hours postdose in the 22.5/3.2 mg/kg Q 12hr regimen amoxicillin plasma concentrations approached or exceeded the MIC reported for B. anthracis for penicillin/amoxicillin in the majority of children, with the levels below the limit of assay quantitation in only 1 out of 5 patients (20%) at 8 hours.
The dosage regimen of 13.3/3.3 mg/kg Q 8hr affords adequate plasma amoxicillin levels that either approach or exceed the MIC values that have been reported for B. anthracis for penicillin/amoxicillin over the entire dosing interval. Note that, unlike the Q 12hr regimen, there were fewer children in the Q 8hr regimen with plasma amoxicillin concentrations below the lower limit of assay quantitation at the end of the dosing interval (i.e., 1/6 (17%) at 6 hours, 2/6 (33%) at 7 hours, and 3/6 (50%) at 8 hours <0.2mg/mL).
Comments on Clavulanic Acid
Amoxicillin and clavulanate in fixed ratios are currently marketed in the U.S. under the trade name Augmentin®. Various studies have shown that the presence of clavulanate in the combination product does not lead to differences in systemic exposure to amoxicillin. Similarly, amoxicillin does not affect the systemic exposure to clavulanate (15, 16, 17).
Conclusions
From the information obtained and reviewed, a dose of amoxicillin of at least 45 mg/kg/day given in 3 divided doses (i.e., 15 mg/kg Q 8hr) to pediatric patients weighing less than 40 kg should yield an adequate time of
systemic exposure (plasma concentrations) of amoxicillin that is above the MIC for susceptible isolates of B.anthracis for the majority of the dosing interval (i.e., 75%-100%). Daily doses less than 45mg/kg and dosing intervals greater than every 8 hr should not be used for prophylaxis of post-exposure inhalational anthrax.
References:
1. Friedlander, AM, et.al. Postexposure Prophylaxis against Experimental Anthrax. J. Infect. Dis. (1993) 167:1239-1242
2. Kelly, DJ, et. al. Serum Concentrations of Penicillin, Doxycycline, and Ciprofloxacin during Prolonged Therapy in Rhesus Monkeys. J. Infect. Dis. (1992) 166:1184-1187
3. Craig, WA. Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men. Clin Infect Dis (1998) 27:1-12
4. Turnidge, JD. Pharmacodynamics of Beta-Lactams. Clin Infect Dis (1998) 27:10-22
5. Spyker, DA, et.al. Pharmacokinetics of Amoxicillin: Dose Dependence after IV, PO, and IM Administration. Antimicrob. Agents Chemother. (1977) 11(1):132-141
6. Bodey, G and Nance, J. Amoxicillin: In Vitro and Pharmacological Studies. J. Antimicrob. Agents Chemother (1972) 1:358-362
7. Kosmidis, J, et.al. Amoxicillin - Pharmacology, Bacteriology, and Clinical Studies. British J. Clin. Pract. (1972) 26:341-346
8. Croydon, EAP and Sutherland, R. Alpha-amino-p-hydroxyl-benzylpenicillin (BRL-2333): A New Semisynthetic Penicillin. Antimicrob. Agents Chemother (1970) 427-433
9. Neu, HC. Amoxicillin. Ann Int Med (1979) 90:356-360
10. Gordon RC, et.al. Comparative Clinical Pharmacology of Amoxicillin and Ampicillin Administered Orally. Antimicrob Agents Chemother. (1972) 1:504-507
11. Brusch, JL, et.al. An In Vitro and Pharmacological Comparison of Amoxicillin and Ampicillin. Amer. J. Med. Sciences (1974) 267(1):41-48
12. Philipson, A, et.al. Sequence Effect on Ampicillin Blood Levels Noted in an Amoxicillin, Ampicillin, and Epicillin Crossover Study. Antimicrob. Agents Chemother. (1975) 8:311-320
13. Zarowny D, et.al. Pharmacokinetics of Amoxicillin. Clin. Pharmacol. Ther. (1974) 16:1045-1051
14. Oliveira CH, et.al. Comparative Bioavailability of 4 Amoxicillin Formulations in Healthy Volunteers after Single Dose Administration. Int J Clin. Pharmacol. Ther. (2001) 39(4):167-172
15. NDA 50-720: Augmentin Oral Tablets, Submission Date October 21, 1994
16. Hampel, B, et. al. Comparative Pharmacokinetics of Sulbactam/Ampicillin and Clavulanic Acid/Amoxicillin in Human Volunteers. Drugs (1988) 35(7):29-33
17. NDA 50-754: Amoxicillin Oral Tablets, Submission Date July 11, 1997
18. Ginsburg, CM, et. al. Comparative Pharmacokinetics of Amoxicillin and Ampicillin in Infants and Children. Pediatrics (1979) 64:627-631
19. NDA 50-725/50-726: Augmentin Oral Suspension/Chewable Tablets, Submission Date May 31, 1995
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