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International Journal of Antimicrobial Agents 30S (2007) S118S121

Development of a twice daily dosing regimen


of amoxicillin/clavulanate
Richard Bax
Consultant in Pharmaceutical Medicine, Churt House, Deerleap Road, Westcott RH4 3LE, UK

Abstract
Amoxicillin/clavulanate was first launched as a three times daily dosage for the treatment of a range of community-acquired infections. A
decade later, it became necessary to introduce a twice daily dosage for reasons of convenience, compliance and to remain competitive with other
recently launched antibacterials. Twice daily formulations of amoxicillin/clavulanate were developed in which the amount of amoxicillin was
increased relative to clavulanate to provide equivalent bacteriological and clinical efficacy with no change in the safety profile. Equivalence of
the two dosing regimens was confirmed by randomised clinical trials in adults (in skin and soft tissue, urinary tract and lower respiratory tract
infections, sinusitis and recurrent tonsillitis) and paediatrics (in lower respiratory tract infections, otitis media and recurrent tonsillitis). An
improvement in the safety profile, specifically gastrointestinal effects, due to the reduced daily dose of clavulanate, was noted for all patients,
but particularly in children.
2007 Published by Elsevier B.V. and the International Society of Chemotherapy.
Keywords: Amoxicillin/clavulanate; Antibiotic resistance; Dosing regimen

1. Introduction
In 1981, amoxicillin/clavulanate was launched as a
three times daily (TID) oral dosage and was used widely
in clinical practice throughout the world for both adults
and children for the treatment of infections of the
upper and lower respiratory tract, the urinary tract, skin
and soft tissue and obstetric, gynaecological and intraabdominal infections. Over time it became apparent that
development of a twice daily (BD) dosage would be
advantageous for a number of reasons. Firstly, compliance was sub-optimal due to the inconvenience of the
midday dose, especially in children. Also, several new
antibiotics had been developed with a once or twice daily
dosing regimen in the decade after launch and amoxicillin/clavulanate needed to remain competitive, although it
was a paramount consideration that efficacy should not be
compromised.

Tel.: +44 1306 742301; fax: +44 1306 883582.


E-mail address: richard.bax@hotmail.co.uk.

2. Development of twice daily amoxicillin/clavulanate


tablets
An adult tablet BD formulation of amoxicillin/clavulanate
was developed in which the proportion of the two agents was
changed from 500 mg amoxicillin/125 mg clavulanic acid to
875 mg amoxycillin/125 mg clavulanic acid (from 4:1 to 7:1).
In vitro bacteriology studies, infection models in vivo and
controlled clinical trials in all indications were carried out
to confirm that the BD dosage had equivalent efficacy to the
TID dosage and a non-inferior safety profile.

3. In vitro studies
Studies were conducted which demonstrated bacteriological equivalence of the BD and TID formulations of
amoxicillin/clavulanate. These studies involved an increase
in the concentration of amoxicillin whilst the concentration
of clavulanate remained constant for each dose resulting
in an increase in bacterial growth inhibition times. Clavulanate inhibits beta-lactamases at very low concentrations

0924-8579/$ see front matter 2007 Published by Elsevier B.V. and the International Society of Chemotherapy.
doi:10.1016/j.ijantimicag.2007.09.002

R. Bax / International Journal of Antimicrobial Agents 30S (2007) S118S121

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Fig. 1. Theoretical free drug serum concentration time curve for amoxicillin/clavulanate 500 mg TID and 875 mg BD.

and has a post-beta-lactamase-inhibitory effect facilitating


less frequent dosing [1,2]. Importantly, equivalent bacterial
eradication by amoxicillin/clavulanate 875/125 mg BD and
amoxicillin/clavulanate 500/125 mg TID was demonstrated
in laboratory models simulating human serum pharmacokinetics [3].

tance selection) [6]. These periods depend on the elimination


half life of the drug. For the BD dosage regimen of amoxicillin/clavulanate, per treatment per day, there are only two
potential periods of selection, whereas for the TID dosage
regimen there are three (Fig. 2). This, coupled with the laboratory bacteriological efficacy of the amoxicillin/clavulanate
BD regimen, suggested that it should not be a greater driver
for the selection of resistance.

4. In vivo studies
Evolving pharmacokinetic and pharmacodynamic principles showed that penicillins exhibit time-dependent killing,
for which there is a good correlation between the time free
plasma concentrations are maintained above the minimum
inhibitory concentration (MIC) and bacteriological eradication such that free plasma concentrations must be above the
MIC for some 40% of the dose interval [4]. The MIC90 for key
respiratory pathogens, i.e. S. pneumoniae, H. inuenzae and
M. catarrhalis, was 2 g/mL for amoxicillin/clavulanate.
For both the 875 mg BD and 500 mg TID regimens, the
amoxicillin free plasma concentrations remained above the
target MIC level for approximately 40% of the dosing interval
(Fig. 1) hence predicting potential equivalent bacteriological
efficacy [5]. Infection models showed equivalent bacterial
eradication in vivo for both formulations and similarly, in
experimental infection models simulating human serum pharmacokinetics, there were equivalent outcomes [3].

6. Randomised clinical studies using BD


amoxicillin/clavulanate
Pre-clinical evidence of equivalence of the BD amoxicillin/clavulanate and TID amoxicillin/clavulanate regimens
produced from in vitro studies and in vivo animal models was
used as a basis for a range of randomised clinical trials.

5. Implications for resistance liability


With increasing antibiotic resistance to major pathogens
globally, it was important that the new BD dosing
regimen did not increase the resistance liability for amoxicillin/clavulanate. Selection of resistant strains occurs during
periods of sub-optimal antibiotic concentration below the
MIC of the pathogen (a window of opportunity for resis-

Fig. 2. Windows of opportunity for selection of resistant organisms [6].

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R. Bax / International Journal of Antimicrobial Agents 30S (2007) S118S121

Table 1
Randomised clinical trials in adults comparing amoxicillin/clavulanate TID and BD dosage regimens
Indication

Number of patients

Skin and soft tissue [7]


UTI [8]
LRTI [9]
Sinusitis [10]
Recurrent tonsillitis [11]

432
634
557
171
370

Dose (mg) amoxicillin/clavulanate

Clinical efficacy (%)

TID

BD

TID

BD

250/125
500/125
500/125
500/125
500/125

500/125
875/125
875/125
875/125
875/125

90.4
96.5
94.3
87.7
97.9

90.2
95.7
93.4
93.4
98.6

BD, twice daily dosage; TID, three times daily dosage.


Table 2
Randomised clinical trials in paediatrics comparing amoxicillin/clavulanate TID and BD dosage regimens
Indication

LRTI [12]
Otitis media (EU) [13]
Otitis media (USA) [14]
Recurrent tonsillitis [15]

Number of patients

437
868
463
495

Dose (mg/kg/day) amoxicillin/clavulanate

Clinical efficacy (%)

TID

BD

TID

BD

20/5
40/10
60/15
30/7.5

25/3.6
45/6.4
70/10
35/5

77.8
78.8
90.5
96.0

81.0
86.5
91.8
97.2

BD, twice daily dosage; TID. three times daily dosage.

6.1. Clinical trials in adults


Five clinical trials (Table 1) in adults [711], involving
over 2100 patients, compared the bacteriological and clinical
efficacy of the BD and TID doses of amoxicillin/clavulanate.
No significant difference was seen between the BD and TID
regimens in the bacteriological and clinical success rates
in any of the infections. A small reduction in diarrhoea
was noted for the BD dosage when compared to the TID
regimen.

reported significantly less moderate to severe diarrhoea


(3.7%) than did those receiving amoxicillin/clavulanate
TID (6.3%) [17]. Paediatric studies in which amoxicillin/clavulanate was used for the treatment of acute otitis
media also confirmed that the BD formulation is well
tolerated. In a study where children were treated with
amoxicillin/clavulanate 45/6.4 mg/kg/day BD or amoxicillin/clavulanate 40/10 mg/kg/day TID, the BD formulation
was significantly better tolerated [18].

6.2. Clinical trials in paediatrics

7. Conclusions

Clinical success rates from four comparative paediatric trials [8,1214] (Table 2) show the clinical equivalence between
the BD (7:1) and corresponding TID (4:1) dosages. Tolerability was improved by reducing the number of doses
per day. Use of the BD dosage regimen resulted in a
reduction in the incidence of diarrhoea: for example, in a
study involving the treatment of otitis media in children
the incidence of diarrhoea was 26.7% in patients receiving
amoxicillin/clavulanate TID for 10 days compared with 9.6%
in those receiving the BD dosage for 10 days (p < 0.0001)
[13].

The introduction of BD dosage of amoxicillin/clavulanate


had several advantages over TID dosage including increased
convenience, improved compliance, and improved tolerability. The amoxicillin component was increased to allow BD
dosage amoxicillin/clavulanate to provide the same bacteriological and clinical efficacy as the original TID dosage. The
unit dose of clavulanate remained unchanged (but was given
twice a day not three times a day) and was sufficient to protect
amoxicillin from the action of beta-lactamase. Introduction of
amoxicillin/clavulanate BD ensured the efficacy and competitiveness of amoxicillin/clavulanate in an environment where
BD dosage was becoming commonplace.

6.3. Safety prole


Amoxicillin/clavulanate is well tolerated and the incidence of adverse events is generally low. In a review
of 374 clinical trials involving amoxicillin/clavulanate
TID therapy in nearly 325 000 patients the overall
incidence of gastrointestinal adverse events was 8.4%
with diarrhoea being the most common [16]. In adult
patients undergoing treatment for lower respiratory tract
infections, patients receiving amoxicillin/clavulanate BD

Acknowledgments
This article is based on a paper presented at a
GlaxoSmithKline-sponsored symposium entitled Augmentin Heritage in Evolving Antibacterial Therapy held on
4th November 2006, London, UK. The assistance in developing the manuscript provided by Stella Deane was funded
by GlaxoSmithKline.

R. Bax / International Journal of Antimicrobial Agents 30S (2007) S118S121

Funding: This study was performed and funded by


SmithKline Beecham.
Competing interests: None declared.
Ethical approval: Relevant ethical approval was granted
as required in each centre and country.
References
[1] Cooper CE, Slocombe B, White AR. Effect of low concentrations
of clavulanic acid on the in vitro activity of amoxycillin against
-lactamase-producing Branhamella catarrhalis and Haemophilus
inuenzae. J Antimicrob Chemother 1990;26:37180.
[2] Thorburn CE, Molesworth MC, Sutherland R, Rittenhouse S. Post
antibiotic and post--lactamase effect of amoxicillin plus clavulanate.
Antimicrob Agents Chemother 1996;40:2796801.
[3] Woodnutt G, Berry V. Two pharmacodynamic models for assessing
the efficacy of amoxicillin-clavulanate against experimental respiratory tract infections caused by strains of Streptococcus pneumoniae.
Antimicrob Agents Chemother 1999;43:2934.
[4] Jacobs MR. Anti-infective pharmacodynamics maximizing
efficacy, minimizing toxicity. Drug Discov Today 2004;1:505
12.
[5] Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections.
J Chemother 1997;9(Suppl. 3):3844.
[6] Baquero F, Negri MC. Strategies to minimize the development of antibiotic resistance. J Chemother 1997;9(Suppl. 3):2937.
[7] Sperling M, Loveless M, SSSI Collaborative Study Group. BID
amoxicillin/clavulanate (A/C) versus TID A/C in the treatment
of uncomplicated skin/skin structure infections. Proc 35th ICAAC
(Abstract LM41).
[8] Study 233. Data on file, GlaxoSmithKline.

S121

[9] Calver AD, Walsh NS, Quinn PF, et al. Dosing of amoxicillin/clavulanate given every 12 h is as effective as dosing every 8 h
for treatment of lower respiratory tract infections. Clin Infect Dis
1997;24:5704.
[10] Seggev JS, Enrique RR, Brandon ML, et al. A combination of
amoxicillin and clavulanate every 12 h vs every 8 h for treatment of
acute bacterial maxillary sinusitis. Arch Otolaryngol Head Neck Surg
1998;124:9215.
[11] Weich-Jung C, Quinn P, ODoherty B, et al. Efficacy of a twice daily
dosing of Augmentin in recurrent tonsillitis. Proc Eur Congr Chemother
1996, Glasgow;W178.
[12] Cook RC, Zachariah J, Cree F, Harrison HE. Efficacy of twice-daily
amoxycillin/clavulanate (Amoxycillin-Duo 400/57) in mild to moderate lower respiratory tract infection in children. Br J Clin Prac
1996;50:1258.
[13] Hoberman A, Paradise JL, Burch DJ, et al. Equivalent efficacy and
reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis
media in children. Pediatr Infect Dis J 1997;16:46370.
[14] Behre U, Burow HM, Quinn P, Cree F, Harrison HE. Efficacy of twice
daily dosing of amoxycillin/clavulanate in acute otitis media in children. Infection 1997;25:1636.
[15] Study 330. Data on file, GlaxoSmithKline.
[16] Neu HC, Wilson APR, Grvneberg RN. Amoxycillin/clavulanic acid:
a review of its efficacy in over 38,500 patients from 1979 to 1992. J
Chemother 1993;5:6793.
[17] Calver A, Walsh N, Quinn P, LRTII Collaborative Study Group. Amoxicillin/clavulanate (A/C) BID vs A/C TID in the treatment of lower
respiratory tract infections (LRTI). Proc 35th ICAAC 1995 (Abstract
LM43).
[18] Aronovitz G, Hoberman A, Drehobl M, Hendrick J, Collaborative
Otitis Media Study Group. Improved safety profile of new paediatric
amoxycillin/clavulanate in acute otitis media. Proc 35th ICAAC 1995
(Abstract LM42).