The Power of Amoxyclav



In 1970s, when combining the broad-spectrum antibiotic amoxicillin with the beta-lactamase inhibitor clavulanic acid proved a highly effective answer to the dual problems of emerging penicillin resistance and increased mixed infection. A solution for all these problems was in the hands of fervent physicians in the year 1981. 

“The amoxicillin and clavulanate combination kept the activity of amoxicillin against streptococci, including pneumococci, but restored the activity of amoxicillin against beta-lactamase producing organisms, such as staphylococci, Escherichia coli and Haemophilus influenzae, and extended its activity against klebsiella and Bacteroides fragilis infections,”.

Combating resistance
Even with its exceptionally striking bioavailability and bactericidal activity, unaided Amoxicillin’s ß-lactam ring proved just as easy a target for bacterial ß-lactamases as its predecessors.

“By 1965, the frequency of clinical isolates producing ß-lactamases had risen dramatically, and it was shown that the ability to make the enzymes was transferred between bacteria via plasmids. This meant that resistance could be spread very rapidly and even passed between different species of bacteria,” explains Professor Geddes.

Researchers went to work to find a solution. Large scale screening of micro-organisms that could produce ß-lactamase inhibitors got under way in 1967 but it took five years for the scientists to find what they were looking for. This was clavulanic acid. Produced by Streptococcus clavuligerus, clavulanic acid was a ß-lactam molecule with low antibacterial activity but whose ß-lactam ring was shown to bind irreversibly to bacterial ß-lactamase, preventing it from inactivating ß-lactam antibiotics.

Combination
Amoxicillin was chosen to be co-administered with clavulanic acid because of its good oral absorption and broad spectrum antimicrobial activity and in early trials in patients with urinary tract infection caused by amoxicillin-resistant bacteria, cure rates of up to 70 per cent were achieved.

“Getting the right dose of amoxicillin proved important for efficacy and getting the right dose of clavulanic acid was key to tolerability,” recalls Professor Geddes.

“Increasing the amoxicillin dose from 250mg every eight hours to 500mg doubled the efficacy in amoxicillin resistant organisms from a disappointing 30 per cent to 70 per cent. But doubling the dose of clavulanic acid from 125 mg every eight hours to 250mg was associated with a 40 per cent prevalence of nausea with no further improvement in cure rate,” he adds.

The further studies established the benefits of the novel amalgamation in respiratory, soft tissue and venereal infections.

Optimizing efficacy
Today, Co-Amoxiclav is most commonly used Universally in the treatment of community-acquired infections, notably respiratory tract infections. Though introduced in a three times daily dose of amoxicillin 250mg/clavulanic acid 125mg, an amoxicillin 500mg/clavulanic acid 125mg dosage soon followed.

In some of the countries, even higher doses of amoxicillin (875mg and 1,000mg) were introduced for severe infection, but the clavulanic acid dose remained the same. More convenient twice daily formulations of 500/125mg and 875/125mg co-amoxiclav are now being promoted and selling in some countries, and twice daily dosages of paediatric formulations are also available.

In the 1990s, research showed that the bacteriological efficacy of ß-lactams is associated with the time that free serum levels remain above the minimum inhibitory concentration (MIC). In animal models of S pneumoniae infection, it was shown that the level of amoxicillin needed to remain above the MIC for 30 to 40 per cent of the dosing interval for maximal bacteriological activity.

Based on pharmacokinetic and pharmacodynamic predictions, it was calculated that amoxicillin/clavulanic acid 875/125mg twice daily would achieve maximal bacteriological efficacy against strains with amoxicillin or amoxicillin/ clavulanic acid MICs equal to or greater than 2mg/L but not equal to or greater than 4mg/L, although the 875/125mg three times daily and 1,000/125mg three times daily regimens were likely to have some efficacy against strains with MICs of 4mg/L.7

To address the need for more long-lasting blood levels against isolates with high MICs, a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid 2,000mg/125mg, was developed, taken as two 1,000mg/62.5mg tablets twice daily. This used a bilayer system to deliver an immediate and an extended release component, the latter flattening the concentration curve and increasing the time that amoxicillin levels remained above the MIC to 49 per cent in isolates with an MIC greater than 4mg/L, and 35 per cent in those with an MIC over 8mg/L.8 This formulation was subsequently approved in the US and some European countries for the treatment of adult respiratory tract infection due to resistant pathogens, but not in the UK, where the prevalence of S pneumoniae strains resistant to amoxicillin/clavulanic acid tends to be lower than in many countries.

Optimizing efficacy
While guidelines discourage antibiotic use for self-limiting respiratory infections, they do advise prompt use in high risk patients and in those who are systemically very unwell or show signs of pneumonia or other complications. It is, therefore, reassuring that a recent analysis of susceptibility data of lower respiratory tract isolates of S pneumoniae, S aureusand H influenzae from sentinel microbiology laboratories in England, Wales and Northern Ireland showed that 92 per cent of isolates were susceptible to co-amoxiclav.

As Professor Geddes concludes: “The rationale for using the combination of amoxicillin and clavulanic acid remains the same today as it was around 40 years ago when it was Introduced. It has an important and unique role to play in the treatment of a range of community-acquired respiratory and other infections.”

It is the Manufacturing Process Which Makes the difference.
For Example - The Carbon gets converted in cheap coal or priceless Diamond, Because of the process it undergoes


Likewise the AMOXYCILLIN + CLAVULANIC ACID combination, which is highly process sensitive product.

NORMAL MANUFACTURING PROCESS
> Swollen tablet cavity
> Discoloration of tablet (Cream>Brown>Black)
> Unstable / Significant reduction in assay of calv
> Wide reduction in dissolution profile
SPECIAL MANUFACTURING PROCESS
> Normal tablet cavity
> White tablet (Throughout the shelf life)
> Stable / insignificant reduction in assay of calv
> Better dissolition profile with constant
   bioavailability











 

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