Probability of Target Attainment and Cumulative Fraction of Response Analysis

Due to the usage of levofloxacin in the treatment of lung infections, such as CAP [19, 20], the adequacy of levofloxacin dosing regimens recommended for the treatment of CAP [21] was evaluated by probability of target attainment (PTA) analysis, a pharmacometric tool aimed at optimising dosing regimens of anti-infectives with the goal of improving therapeutic outcome and preventing the emergence and spread of resistance [33]. For this purpose, Monte Carlo simulations (n = 1000 per covariate combination) of levofloxacin concentration over time in plasma were performed for the integral-CA and midpoint-CA models for different dosing regimens. To cover a broad range of PK/PD targets and MIC values reported for levofloxacin by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), PTA for achieving the CAP-related PK/PD target fAUC_0–24/MIC≥34 [34] was calculated for MIC = 0.100–4.00 mg/l [35]. A plasma protein binding of 31.0%, the average across reported values, was selected for calculation of unbound levofloxacin concentrations [36–39]. PTA was calculated using the percentage of the simulated individuals who were at or above the PK/PD target at each MIC. A dosing regimen was considered adequate if PTA≥90%.

The adequacy of levofloxacin dosing regimens was additionally evaluated against the most prevalent CAP-associated pathogens (Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae) [35, 40]. For this purpose, the cumulative fraction of response (CFR) according to [41] was calculated by multiplying PTA by the cumulative proportion of bacterial isolates at each MIC from EUCAST (MIC = 0.001–512 mg/l).

To consider relevant dosing regimens for the treatment of CAP, once- and twice-daily intravenous short-term (30 min) infusions of 500 mg levofloxacin were evaluated [21].