New Approaches to the Optimization of Antimicrobial Therapy of Respiratory Tract Infections Using Pharmacokinetic and Pharmacodynamic Parameters

Abstract

To understand the relationship between drug dose and efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics need to be integrated. There are two patterns of antimicrobial activity: time-dependent killing and concentration-dependent killing. Time-dependent killing is characteristic of β-lactams and some macrolides. The major PK/PD parameter correlating with efficacy of time-dependent antimicrobials is the serum concentration present for 40–50% of the dosing interval, and this concentration is the susceptibility limit or breakpoint for the dosing regimen used. Concentration-dependent killing is seen with aminoglycosides, quinolones, some macrolides and azalide. The major PK/PD parameter correlating with efficacy of these agents is the 24-hour area under the curve to MIC ratio, which should be ≥25 for less severe infections (≥100 in more severe infections or in immunocompromised hosts). PK/PD breakpoints for concentration-dependent agents can therefore be calculated from the formula AUC/25. For an antimicrobial to be useful empirically the MIC90 of the agent against the common pathogens responsible for the disease being treated should be below the PK/PD breakpoint. This is particularly important for oral therapy of respiratory tract infections, where efficacy against predominant pathogens (S. pneumoniae and H. influenzae, including strains with emerging resistance) is required. PK/PD principles have been applied to recent Russian isolates of these species in this article.