Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae.

The development of our understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine antimicrobial efficacy has advanced substantially over the last 10 years. We are now in a position to use PK/PD principles to set targets for antimicrobial design and optimisation so that we can predict eradication of specific pathogens or resistant variants when agents are used clinically. Optimisation of PK/PD parameters to enable the treatment of resistant pathogens with oral agents may not be possible with many current agents, such as some cephalosporins, macrolides and fluoroquinolones. Aminopenicillins, however, such as amoxicillin, have linear PK and have a good safety profile even at high doses. The new pharmacokinetically enhanced oral formulation of amoxicillin/clavulanate, 2000/125 mg twice daily, was designed using PK/PD principles to be able to eradicate Streptococcus pneumoniae with amoxicillin MICs of up to and including 4 mg/L, which includes most penicillin-resistant isolates. For amoxicillin and amoxicillin/clavulanate, a time above MIC (T > MIC) of 35-40% of the dosing interval (based on blood levels) is predictive of high bacteriological efficacy. This target was met by the design of a unique bilayer tablet incorporating 437.5 mg of sustained-release sodium amoxicillin in one layer plus 562.5 mg of immediate-release amoxicillin trihydrate and 62.5 mg of clavulanate potassium in the second layer, with two tablets administered for each dose. This unique design extends the bacterial killing time by increasing the T > MIC to 49% of the dosing interval against pathogens with MICs of 4 mg/L, and 60% of the dosing interval against pathogens with MICs of 2 mg/L. Based on these results, this new amoxicillin/clavulanate formulation should be highly effective in treating respiratory tract infections due to drug-resistant S. pneumoniae as well as beta-lactamase-producing pathogens, such as Haemophilus influenzae and Moraxella catarrhalis.