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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.
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
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Fig. 1. Theoretical free drug serum concentration time curve for amoxicillin/clavulanate 500 mg TID and 875 mg BD.
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].
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Table 1
Randomised clinical trials in adults comparing amoxicillin/clavulanate TID and BD dosage regimens
Indication
Number of patients
432
634
557
171
370
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
LRTI [12]
Otitis media (EU) [13]
Otitis media (USA) [14]
Recurrent tonsillitis [15]
Number of patients
437
868
463
495
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
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].
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.
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for treatment of lower respiratory tract infections. Clin Infect Dis
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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.
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Otitis Media Study Group. Improved safety profile of new paediatric
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(Abstract LM42).