Pharmacokinetic optimisation of β-lactams for the treatment of ventilator-associated pneumonia

Rational therapy of ventilator-associated pneumonia requires choosing the right drug at the right dose. The choice of dose depends on the microbiological goal, the range of minimum inhibitory concentrations (MICs) for likely pathogens, the extent of the drug's protein binding and, in humans, pharmacokinetics. If protein binding and the distribution of pharmacokinetic parameters are known, as well as the likely pathogens and MICs in a given setting, Monte Carlo simulations can be used to calculate the likelihood that a given dose will attain an identified microbiological goal. For beta-lactams, the antibacterial effect depends on the percentage of time (% T) during the dosing interval that the free (nonprotein bound) antibiotic concentration remains above the MIC (% T. MIC); the required values are smaller for carbapenems than for penicillins or cephalosporins. Data show that infusion of an i.v. beta-lactam over an extended period may greatly increase % T. MIC, and hence efficacy, at a given dose. Alternatively, it may provide the same efficacy at a lower total dose, reducing cost and potential toxicity. In a real-life setting, a 4-h infusion of 3.375 g piperacillin-tazobactam q8 h (every 8 h; 3 times daily); proved more effective for severe Pseudomonas aeruginosa infections than a 30-min infusion of 3.375 g q6 h (every 6 h; 4 times daily) or q4 h (every 4 h; 6 times daily). Data for doripenem, an investigational carbapenem, suggest that its stability following reconstitution may render it particularly suitable for extended infusion.