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Amoxicillin/Clavulanic Acid

A Review of its Use in the Management of Paediatric Patients with Acute Otitis Media

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Summary

Abstract

Amoxicillin/clavulanic acid (Augmentin®, Augmentin ES-600™)1 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a β-lactamase inhibitor).

Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and β-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains.

Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age ≈2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age ≈1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age ≈1 year).

The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L).

Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial.

Conclusions: Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC ≤2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent p aediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

Antibacterial Activity

Amoxicillin/clavulanic acid is a well established antibacterial agent which is active against a wide range of Gram-positive and Gram-negative bacteria, including the main causative pathogens of paediatric acute otitis media (AOM). The addition of clavulanic acid extends the spectrum of amoxicillin to include β-lactamase-producing pathogens such as Haemophilus influenzae and Moraxella catarrhalis. Amoxicillin/clavulanic acid shows good in vitro activity against penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae (median minimum inhibitory concentration against 90% of isolates [MIC90] 0.03 and 1 mg/L), but more moderate activity against penicillin-resistant S. pneumoniae (median MIC90 4 mg/L) [National Committee for Clinical Laboratory Standards breakpoints for amoxicillin/clavulanic acid are: susceptible ≤2/l, intermediate 4/2 and resistant ≥8/4 mg/L]. Median amoxicillin/clavulanic acid MIC90 values for penicillin-susceptible, -intermediate and -resistant strains of Streptococcus pneumoniae were lower than those for cefpodoxime, cefuroxime, azithromycin and clarithromycin.

Amoxicillin/clavulanic acid and MIC90 values against β-lactamase-positive or -negative strains of H. influenzae (median MIC90 2 and 1 mg/L) were broadly similar to that for cefuroxime and markedly lower than those for azithromycin or clarithromycin, but higher than for cefpodoxime.

In a single study, the amoxicillin/clavulanic acid MIC90 against β-lactamase-positive M. catarrhalis (0.5 mg/L) was lower than that for cefpodoxime and cefuroxime but greater than that for azithromycin and clarithromycin.

Amoxicillin/clavulanic acid had the lowest MIC90 value of any of the agents evaluated against β-lactamase-negative isolates of M. catarrhalis in this analysis. In a rat model of pneumonia that evaluated the activity of amoxicillin/clavulanic acid against penicillin-resistant strains of S. pneumoniae, a dosage equivalent to 45/6.4 mg/kg/day was only fully effective against strains with aMIC of 2 mg/L, whereas a dosage equivalent to 90/6.4 mg/kg/day significantly reduced bacterial numbers in the lungs for strains with amoxicillin MIC values of 2 or 4 mg/L.

Pharmacokinetic Properties

The oral bioavailability of amoxicillin is about 70 to 90% and maximum serum concentrations occur within 60 to 90 minutes of administration. Clavulanic acid shows more variable oral bioavailability of 31 to 99%. Serum concentration profiles for amoxicillin and clavulanic acid are broadly similar in infants and children regardless of formulation/dosage ratio.

Amoxicillin/clavulanic acid provides appropriate drug exposure against penicillin-susceptible strains of S. pneumoniae, H. influenzae and M. catarrhalis (based on the time, as a proportion of the dose interval, for which plasma drug concentration exceeded the MIC90 [T > MIC]). In an analysis based on the published literature for selected agents used to treat AOM, amoxicillin (40 mg/kg/day in three divided doses) had the highest overall coverage of any oral agent for penicillin-intermediate strains of S. pneumoniae (T > MIC90 = 59%) and was the only oral agent to provide adequate coverage for penicillin-resistant S. pneumoniae (T > MIC90 = 46%). Other agents evaluated were cefprozil, cefuroxime, cefpodoxime, loracarbef, cefaclor and cefixime.

Amoxicillin and clavulanic acid are well distributed into most body tissues and extracellular fluids, including middle-ear mucosa and middle-ear effusions in children. Effective antibacterial concentrations of both drugs are achieved in the middle ear.

Like most other β-lactam antibacterial agents, a large proportion of amoxicillin (50 to 80%) is primarily excreted unchanged in the urine within 6 hours of administration. Clavulanic acid appears to undergo more extensive metabolism with only 20 to 60% of unchanged drug eliminated in this way. The mean elimination half-lives of amoxicillin and clavulanic acid are each about 1 hour, and the mean total clearance of both is about 25 L/h in healthy adult volunteers.

Therapeutic Efficacy

The most common pathogens isolated by tympanocentesis in trials in patients with AOM were Staphylococcus pneumoniae, H. influenzae and M. catarrhalis (S. pyogenes and Staphylococcus aureus were less commonly detected).

Amoxicillin/clavulanic acid 300 to 450 mg/day in three divided doses showed good clinical efficacy (88% of patients assessed as cured) in two postmarketing studies in 3048 children ≤14 years of age with AOM.

Amoxicillin/clavulanic acid 45/6.4 or 70/10 mg/kg/day in two divided doses produced similar clinical response rates to 40/10 or 60/15 mg/kg/day in three divided doses in infants and children with AOM in three multicentre, randomised, single-blind trials.

Amoxicillin/clavulanic acid (mostly 40 mg/kg/day in three divided doses) produced clinical response rates similar to those for oral cephalosporin comparators (cefuroxime axetil, cefdinir, cefaclor, cefixime, cefpodoxime proxetil, cefprozil and ceftibuten) in numerous multicentre, randomised AOM trials (mean patient age ≈2 to 5 years). Clinical response rates were similar to (two trials) or significantly greater than (one trial) those for intramuscular ceftriaxone. For comparators assessed in more than one trial, clinical response rates were 74 to 88% with amoxicillin/clavulanic acid versus 70 to 86% with cefuroxime axetil, 82 to 95% versus 74 to 95% with intramuscular ceftriaxone and 86 and 90% versus 80 and 91% for cefdinir.

Clinical response rates were generally similar for amoxicillin/clavulanic acid (mostly 40mg/kg/day in three divided doses) and the macrolide antibacterials azithromycin (86 to 100% vs 70 to 100%) and clarithromycin (92 to 97% vs 90 to 96%) [mean patient age ≈1 to 6 years], although a significantly higher response was seen for amoxicillin/clavulanic acid compared with azithromycin in a single randomised trial. Significantly greater bacteriological efficacy with amoxicillin/clavulanic acid was also reported in the latter study.

Successful bacterial eradication, including that of penicillin-resistant S. pneumoniae, was demonstrated with the new high-dose formulation of amoxicillin/ clavulanic acid (90/6.4 mg/kg/day in two divided doses) in a multicentre non-comparative trial in 521 children with AOM aged between 3 and 48 months (mean ≈1.6 years). Pathogens were eliminated from 96% of bacteriologically evaluable patients. This included 91% (published data) or 94% (data from package insert) of patients with penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L). For patients with baseline-isolate penicillin MICs of 2 mg/L (the upper limit of the US indication for S. pneumoniae) eradication rates were 19 of 20 (published) and 19 of 19 (package insert).

High-dose (90/6.4 mg/kg/day) and conventional (45/6.4 mg/kg/day) amoxicillin/clavulanic acid regimens given in two divided doses produced similar clinical response rates (84 and 79% of patients had persistent clinical cure with no recurrence) in a double-blind multicentre study designed primarily to assess tolerability (n = 453).

Tolerability

Amoxicillin/clavulanic acid is generally well tolerated. The most frequently reported adverse events are gastrointestinal (GI) disturbances, including diarrhoea, nausea, vomiting and indigestion. The incidence of diarrhoea was significantly reduced (one study) or tended to be lower (two studies) for twice-daily compared with three-times-daily amoxicillin/clavulanic acid regimens in randomised single-blind studies.

In randomised trials in paediatric patients with AOM, amoxicillin/clavulanic acid generally produced total adverse event rates that were not significantly different from those of cephalosporin comparators (range 3.1 to 63% vs 3.4 to 44%). In the majority of studies, total and GI adverse event rates were significantly higher with amoxicillin/clavulanic acid than with macrolide comparators, although most used a three-times-daily amoxicillin/clavulanic acid regimen (which tends to cause more diarrhoea). Total adverse event rates ranged from 3.7 to 51 % for amoxicillin/clavulanic acid and from 2 to 32% for macrolide comparators.

No serious adverse events and a low total incidence of events (3.6%) were reported during postmarketing surveillance of 3048 children aged ≤14 years with AOM who received amoxicillin/clavulanic acid 300 to 450 mg/day in three divided doses.

High-dose amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) had a similar tolerability profile to a conventional twice-daily regimen (45/6.4 mg/kg/day in two divided doses) in a randomised, double-blind trial in 408 children with AOM. Adverse events were reported in a total of 50.2 and 47.3% of patients, with protocol-defined diarrhoea in 11 and 8.8%. The most frequently reported adverse events in 521 children treated with the high-dose formulation in a noncomparative trial were diaper rash (4.0%), diarrhoea (3.6%), vomiting (2.3%) and other rash (1.3%). Events probably or possibly related to the medication were documented in 14% of patients.

Dosage and Administration

Amoxicillin/clavulanic acid is available in a range of formulation and dosage combinations, including oral suspension, chewable tablets and tablets. The standard regimen for paediatric patients aged 3 months or above is 45/6.4 mg/kg/day in two divided doses for 10 days. In the US, conventional formulations of amoxicillin/clavulanic acid (maximum amoxicillin: clavulanic acid ratio 7:1) are indicated for the treatment of AOM caused by β-lactamase-producing strains of H. influenzae and M. catarrhalis.

The high-dose amoxicillin/clavulanic acid formulation allows administration at 90/6.4 mg/kg/day in two divided doses, double the previously recommended standard amoxicillin dosage for paediatric patients aged 3 months or above. It is indicated for the treatment of paediatric patients with recurrent or persistent AOM due to S. pneumoniae (penicillin MICs ≤2 mg/L), H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains) characterised by the following risk factors: antibiotic exposure for AOM within the preceding 3 months, and either age ≤2 years or attendance at daycare.

Amoxicillin/clavulanic acid should be used cautiously in patients with hepatic impairment. Dosage adjustment is recommended for patients aged <3 months.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Jane Easton, Stuart Noble & Caroline M. Perry

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  1. Jane Easton
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  2. Stuart Noble
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  3. Caroline M. Perry
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Correspondence to Stuart Noble.

Additional information

Various sections of the manuscript reviewed by: A.M. Cuffini, Department of Public Health and Microbiology, University of Turin, Turin, Italy; M.R. Jacobs, Department of Pathology, University Hospitals of Cleveland, Cleveland, Ohio, USA; S.D. Subba Rao, Departmnt of Pediatrics, St. John’s Medical College Hospital, Bangalore, India; M.E. Pichichero, Department of Pediatrics and Medicine, University of Rochester Medical Center, Rochester, New York, USA; C. Thornsberry, MRL Pharmaceutical Services, Brentwood, Tennessee, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on amoxicillin/clavulanic acid and otitis media, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘amoxicillin/clavulanic acid’ and ‘otitis media’. EMBASE search terms were ‘amoxicillin/clavulanic acid’ and ‘otitis media’. AdisBase search terms were ‘amoxicillin clavulanic acid’ and ‘otitis media’. Searches were last updated 17 Dec 2002.

Selection: Studies in patients with acute otitis media who received amoxicillin/clavulanic acid. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: acute otitis media, AOM, amoxicillin/clavulanic acid, pharmacodynamics, pharmacokinetics, therapeutic use, antibacterial.

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Easton, J., Noble, S. & Perry, C.M. Amoxicillin/Clavulanic Acid. Drugs 63, 311–340 (2003). https://doi.org/10.2165/00003495-200363030-00005

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